CN105073742A - Flap modulators - Google Patents

Abstract

The present invention relates to compounds of Formula (I), or a form thereof, wherein ring A, R1, L and R2 are as defined herein, useful as FLAP modulators. The invention also relates to pharmaceutical compositions comprising compounds of Formula (I). Methods of making and using the compounds of Formula (I) are also within the scope of the invention.

Description

FLAP modulator

Cross References to Related Applications

This application claims the benefit of US Provisional Application 61/760,615, filed February 4, 2013, and US Provisional Application 61/798,951, filed March 15, 2013, each of which is incorporated herein by reference in its entirety.

technical field

The present invention relates to substituted compounds useful as modulators of 5-lipoxygenase-activating protein (FLAP), pharmaceutical compositions of such compounds, and methods of their preparation and use. More specifically, FLAP modulators are useful for preventing, treating or ameliorating FLAP-mediated diseases and/or disorders, including those inflammatory diseases and/or disorders associated with dermatological disorders and respiratory disorders, allergic disorders, autoimmune, Cancer, cardiovascular and metabolic disorders.

Background technique

FLAP is a key initiator of the leukotriene synthesis pathway, which binds arachidonic acid and subsequently converts it into 5-lipoxygenase (M. Abramovitz et al., "5-lipoxygenase-activating proteins stimulates the utilization of arachidonic acid by 5-lipoxygenase," Eur. J . Biochem., 1993, 215, 105-11). FLAP has been shown to interact with LTC ₄ synthase and putatively regulate LTC ₄ production (T. Strid et al., "DistinctpartsofleukotrieneC(4)synthaseinteractwith5-lipoxygenaseand5-lipoxygenaseactivatingprotein," Biochem.Biophys.Res.Comm., 2009, 381(4), 518-22). Modulation (including but not limited to inhibition) or gene deletion of FLAP blocks leukotriene production, especially LTB ₄ , cysteinyl leukotrienes (LTC ₄ , LTD ₄ and LTE ₄ ), and 5-oxo-ETE ( et al., "Lipoxygenase and leukotriene pathways: biochemistry, biology, androles indisease," Chem Rev., 2011, 111(10), 5866-98).

Leukotrienes are immunomodulatory lipids formed from arachidonic acid (see B. Samuelsson, "Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation," Science, 1983, 220, 568-75). It is mainly synthesized by eosinophils, neutrophils, mast cells, basophils, dendritic cells, macrophages and monocytes. Leukotrienes mediate a variety of biological effects including (by way of example only) smooth muscle contraction, leukocyte recruitment and activation, cytokine secretion, fibrosis, mucus secretion, and vascular function ( pp. 5866-5898).

FLAP-deficient mice are healthy and reproduce normally. They do not produce leukotrienes and reduce susceptibility in a mouse model of arthritis (RJ Griffiths et al., "Collagen-induced arthritis is reduced in5-lipoxygenase-activating protein-deficient mice," J. Exp. Med., 1997, 185, 1123-29) . In humans, genetic studies have linked FLAP itself to respiratory disorders and cardiovascular diseases, including myocardial infarction, atherosclerosis, cerebral infarction, coronary artery disease and stroke (A. atherosclerosisandstroke,”Nat.Genet.,2004,36,233–39；ASTulah等人，“TheroleofALOX5AP,LTA4HandLTB4RpolymorphismsindeterminingbaselinelungfunctionandCOPDsusceptibilityinUKsmokers,”BMCMed.Genet.,2011,29(12),173；R.Ji等人，“GeneticvariantsinthepromoterregionoftheALOX5APgeneandsusceptibilityofischemicstroke,”Cerebrovasc. Dis.,2011,32(3),261-68；JWHolloway等人，“TheroleofLTA4HandALOX5APpolymorphisminasthmaandallergysusceptibility,”Allergy,2008,63(8),1046-53；J.Nair等人，“Expressionanalysisofleukotriene-inflammatorygeneinteractionnetworkinpatientswithcoronaryarterydisease,”JAtheroscler.Thromb ., 2013; LFChi et al., “Interaction between ALOX5AP and CYP3A5 gene variants significantly increases risk force rebralin farctions in Chinese,” Neuroreport., 2013). In addition, studies using animal models provide support for the notion that leukotrienes play a major role in aortic aneurysm, atherosclerosis, pulmonary hypertension, myocardial infarction, atherosclerosis, and stroke (see   pp. 5866-5898).

Leukotrienes also play a role in autoimmune disorders such as: rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty exudates, systemic lupus erythematosus, Systemic sclerosis, Alzheimer's disease, and multiple sclerosis (S. - Minarowska et al., "Theroleofleukotrienes in the pathogenesis of systemics clerosis," Folia Histochem. Cytobiol., 2012, 50(2), 180-85; pp. 5866-5898; I. Loell et al., "Activated LTB4 pathway inmusclet issue of patients with polymyositis order matomyositis," Ann. Rheum. Dis., 2013, 72(2), 293-99; J. Chu et al., "Involvement of 5-lipoxygenase activating protein in the amyloidotic pheno" Neuroinflammation, 2012, 9, 127). Leukotrienes are also associated with several aspects of carcinogenesis, including tumor cell proliferation, differentiation, and apoptosis, tumor-associated angiogenesis, and metastasis and invasion of cancer cells (D. Wang and RNDubois, "Eicosanoids and cancer," Nat. Rev. Cancer, 2010 , 10(3), 181-93).

Leukotrienes play a role in allergic disorders such as allergic rhinitis, allergic dermatitis, and asthma, as well as in respiratory disorders such as exacerbated, non-allergic asthma, aspirin-exacerbated respiratory disease, fibrotic lung disease, acute respiratory distress syndrome, and chronic obstructive pulmonary disease. plays a key role in barriers (see JZ pp. 5866-5898). Validated LTC ₄ receptor antagonists and leukotriene synthesis modulators such as zileuton have shown clinical efficacy in a variety of respiratory disorders (see ME Krawiec and SE Wenzel, "Leukotriene modulators and non-steroidal therapies in the treatment of asthma," Expert. Opin. Pharmacotherapy , 2001, 2(1), 47-65).

All of the above evidence provides support for the key role of leukotrienes in various human diseases and/or disorders, and FLAP modulation can be effective in preventing, treating or ameliorating these immune-mediated inflammatory diseases and/or disorders. Furthermore, there remains a need for FLAP modulator compounds with pharmacokinetic and pharmacodynamic properties suitable for use as human pharmaceuticals.

Contents of the invention

In many embodiments of the invention, the invention provides novel compounds useful, for example, as modulators of FLAP (including but not limited to novel compounds that inhibit FLAP), methods of making such compounds, compounds comprising one or more of such Pharmaceutical compositions of compounds, methods of preparing pharmaceutical compositions comprising one or more such compounds, and the use of such compounds or pharmaceutical compositions to prevent, treat, improve (including but not limited to inhibit) one or more Methods for FLAP-associated diseases and/or disorders.

One aspect of the present invention relates to compounds, methods and compositions for the treatment or prevention or amelioration of various diseases and/or disorders mediated or maintained by leukotriene activity, including pulmonary, allergic Sexual, fibrotic, neuropathic, inflammatory, autoimmune and cardiovascular diseases and cancers or their associated symptoms or complications. More particularly, the present invention relates to the treatment of exacerbations, non-allergic asthma, fibrotic lung disease, acute respiratory distress syndrome and chronic obstructive pulmonary disease or their association in subjects suffering from such diseases and/or disorders A method for a symptom or complication, wherein the method comprises administering a FLAP modulator.

Another aspect of the present invention relates to compounds, methods and compositions for treating or preventing or ameliorating heart and cardiovascular diseases and/or disorders, or their associated symptoms or complications, including but not limited to Myocardial infarction, atherosclerosis, stroke and atherosclerotic aortic aneurysm or their associated symptoms or complications in a subject suffering from such diseases and/or disorders, wherein the method comprises administering a FLAP modulator.

In addition, yet another aspect of the present invention relates to methods for preventing, treating or improving autoimmune diseases and/or disorders or their related symptoms or complications (including but not limited to rheumatoid arthritis, inflammatory bowel disease, nephritis, spinal Arthritis, polymyositis, dermatomyositis, gouty exudates, systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease, multiple sclerosis) or allergic disorders (including but not limited to allergic rhinitis, allergic dermatitis and asthma) or their associated symptoms or complications in a subject with such diseases and/or disorders, wherein the method comprises administering a FLAP modulator.

Finally, one aspect of the present invention relates to methods for preventing, treating or ameliorating carcinogenesis (including but not limited to tumor cell proliferation, differentiation, apoptosis, tumor-associated angiogenesis, and cancer cell metastasis and invasion) or their treatment in patients with such diseases Compounds, methods and compositions for related symptoms or complications in a subject with and/or disorder, wherein the method comprises administering a FLAP modulator.

Another aspect of the present invention is characterized by compounds of formula (I) or optical isomers, hydrates, metabolites, enantiomers, diastereomers, cis-trans isomers, racemates, prodrugs thereof or a pharmaceutically acceptable salt,

in

L is a bond: –CH ₂ –, –CH ₂ CH ₂ –, –CH ₂ CH ₂ CH ₂ –, –CH ₂ CH ₂ NH-, –CH ₂ C(=O)NH–, –CH ₂ C(OH )(H)CH ₂ – or –CH ₂ C(OH)(H)CH ₂ NH–;

R is halo, C _1-5 alkyl, C _{3-6 cycloalkyl} or cyclohexylmethyl;

R ₂ is H, C _1-4 alkyl, hydroxyl, amino, cyano, -CH ₂ C(=O)O-(t-butyl), -CH ₂ C(=O)O-(ethyl), -CH ₂ C(=O)OH, -NHS(=O) ₂ CH ₃ , tert-butyl(dimethyl)silyl-oxyl, -NHCH ₃ , -N(CH ₃ ) ₂ , -NH- (isopropyl), optionally substituted phenyl, optionally substituted 5-membered or 6-membered heteroaryl, C _3-6 cycloalkyl, or optionally substituted heterocyclyl;

Wherein the 5-membered or 6-membered heteroaryl, heterocyclyl or phenyl is optionally and independently substituted by 1-4 substituents selected from the following:

C _1-4 alkyl, -CH ₂ -methoxy, -C(=O)OH, -CH ₂ C(=O)OH, -C(=O)-O-CH ₂ CH ₃ , -C( =O)-O-CH ₃ , –C(=O)-O-(tert-butyl), –NH ₂ , –NHCH ₃ , –N(CH ₃ ) ₂ , –NH-(isobutyl), – NH(CH ₂ ) ₂ NHC(=O)-O-tert-butyl, –NH(CH ₂ ) ₂ NH ₂ , –NH(CH ₂ ) ₂ N(CH ₃ ) ₂ , –C(=O)NH ₂ , -C(=O)CH ₃ , oxo, halo, hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy, methoxymethyl, -S(=O) ₂ CH ₃ , –S(=O) ₂ NH ₂ , –S(=O) ₂ NH(CH ₃ ), –S(=O) ₂ N(CH ₃ ) ₂ , –S-CH ₃ , cyano, 1H-tetra Azol-5-yl, thiophen-2-yl, cyclopropyl, azetidin-1-yl, phenyl, 4'-(trifluoromethyl)phenyl, benzyl, 1,5-dioxa- 9-Azaspiro[5.5]undecyl-9-yl, 5-pyrimidin-2-amine and pentafluoro-λ~6~-sulfanyl;

Ring A is selected from:

R ₃ is H, cyano, methyl, methoxy, halo or -NH ₂ ;

R ₄ is H or methyl; and

R ₅ is H, cyano, halo, CF ₃ or —NH ₂ .

Another aspect of the invention features pharmaceutical compositions comprising at least one compound of formula (I) and at least one pharmaceutically acceptable carrier. The present invention also relates to providing a method for formulating a pharmaceutical composition comprising formulating a pharmaceutical composition of at least one compound of formula (I) and at least one pharmaceutically acceptable carrier. The present invention also relates to a process for the preparation of a pharmaceutical composition comprising admixing any of the compounds according to formula (I) with a pharmaceutically acceptable carrier.

The invention also features a method of treating a subject having or being diagnosed with a disease and/or disorder mediated by FLAP activity, the method comprising administering to the subject a therapeutically effective amount of at least one formula (I) compound of. Such diseases and/or disorders may include, but are not limited to, respiratory disorders, heart and cardiovascular diseases, autoimmune disorders, carcinogenesis, or related symptoms or complications. More specifically, the present invention relates to the treatment of exacerbated, non-allergic asthma, fibrotic lung disease, acute respiratory distress syndrome, chronic obstructive pulmonary disease, myocardial infarction, atherosclerosis and stroke aortic aneurysm, atherosclerosis, Rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty exudate, systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease, multiple sclerosis, Allergic rhinitis, allergic dermatitis and asthma, tumor cell proliferation, differentiation and apoptosis, tumor-associated angiogenesis and metastasis and invasion of cancer cells, or their association in subjects with such diseases and/or disorders A method for symptoms or complications, or their associated symptoms or complications, wherein the method comprises administering to a subject in need thereof a FLAP modulator, a therapeutically effective amount of at least one compound of formula (I), preferably Pharmaceutical compositions comprising at least one compound of formula (I).

Additional embodiments and advantages of the present invention will become apparent from the following detailed discussion, scenarios, examples and claims.

Detailed ways

The present invention relates to novel FLAP modulators and compositions thereof for use in the prevention, treatment or amelioration of various diseases and/or disorders including, but not limited to, respiratory diseases and/or disorders, cardiac and cardiovascular diseases and/or disorders, autoimmune diseases and/or disorders, carcinogenesis, and their associated symptoms or complications.

One aspect of the invention is characterized by compounds of formula (I)

in

L is a bond: -CH ₂ -, -CH ₂ CH ₂ -, -CH ₂ C(OH)(H)CH ₂ , -CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ NH-, -CH ₂ C (=O)NH– or –CH ₂ C(OH)(H)CH ₂ NH–;

R is halo, C _1-5 alkyl, C _{3-6 cycloalkyl} or cyclohexylmethyl;

R ₂ is H, C _1-4 alkyl, hydroxyl, amino, cyano, -CH ₂ C(=O)O-(t-butyl), -CH ₂ C(=O)O-(ethyl), -CH ₂ C(=O)OH, -NHS(=O) ₂ CH ₃ , tert-butyl(dimethyl)silyl-oxyl, -NHCH ₃ , -N(CH ₃ ) ₂ , -NH- (isopropyl), optionally substituted phenyl, optionally substituted 5-membered or 6-membered heteroaryl, C _3-6 cycloalkyl or optionally substituted heterocyclyl;

Wherein the 5-membered or 6-membered heteroaryl, heterocyclyl or phenyl is optionally and independently substituted by 1-4 substituents selected from the following:

C _1-4 alkyl, -CH ₂ -methoxy, -C(=O)OH, -CH ₂ C(=O)OH, -C(=O)-O-CH ₂ CH ₃ , -C( =O)-O-CH ₃ , –C(=O)-O-(tert-butyl), –NH ₂ , –NHCH ₃ , –N(CH ₃ ) ₂ , –NH-(isobutyl), – NH(CH ₂ ) ₂ NHC(=O)-O-tert-butyl, –NH(CH ₂ ) ₂ NH ₂ , –NH(CH ₂ ) ₂ N(CH ₃ ) ₂ , –C(=O)NH ₂ , -C(=O)CH ₃ , oxo, halo, hydroxyl, methoxy, trifluoromethyl, trifluoromethoxy, methoxymethyl, -S(=O) ₂ CH ₃ , –S(=O) ₂ NH ₂ , –S(=O) ₂ NH(CH ₃ ), –S(=O) ₂ N(CH ₃ ) ₂ , –S-CH ₃ , cyano, 1H-tetra Azol-5-yl, thiophen-2-yl, cyclopropyl, azetidin-1-yl, phenyl, 4'-(trifluoromethyl)phenyl, benzyl, 1,5-dioxa- 9-Azaspiro[5.5]undecyl-9-yl, 5-pyrimidin-2-amine and pentafluoro-λ~6~-sulfanyl;

Ring A is selected from:

R ₃ is H, cyano, methyl, methoxy, halo or -NH ₂ ;

R ₄ is H or methyl; and

R ₅ is H, cyano, halo, CF ₃ or —NH ₂ .

Some embodiments of the invention are given by compounds of formula ( _I ), wherein R is tert _- butyl, cyclopropyl, cyclobutyl or cyclopentyl, _R is H or cyano, R is H, and _R5 is H.

Further embodiments are given by compounds of formula (I), wherein R ₁ is tert-butyl, cyclobutyl or cyclopentyl.

Additionally, other embodiments are given by compounds of formula (I), wherein R ₁ is tert-butyl or cyclobutyl, R ₃ is H or cyano, R ₄ is H, and R ₅ is H.

Some embodiments are given by compounds of formula (I), wherein Ring A is

In some of these embodiments, wherein Ring A is or _R3 is cyano and R4 is cyano _.

In some of these embodiments, wherein Ring A is or _R3 is H, and _R4 is H.

Some embodiments are given by compounds of formula (I), wherein R ₁ is tert-butyl.

Some embodiments are given by compounds of formula (I), wherein R ₁ is cyclobutyl.

In some of these embodiments, wherein R ₁ is cyclobutyl, R ₂ is -CH ₂ C(=O)O-(tert-butyl), -CH ₂ C(=O)O-(ethyl), -CH ₂ C(=O)OH or -NHS(=O) ₂ CH ₃ .

In some of these embodiments, wherein R ₁ is cyclobutyl, R ₂ is optionally substituted phenyl or optionally substituted 5- or 6-membered heteroaryl.

In some of these embodiments, wherein R ₁ is cyclobutyl and L is a bond or —CH ₂ —.

In some of these embodiments, wherein R is cyclobutyl, Ring _A is or

In some of these embodiments, wherein R is cyclobutyl, Ring _A is or

In some of these embodiments, wherein R is cyclobutyl, Ring _A is

Some embodiments are given by compounds of formula (I), wherein L is a bond or -CH ₂ -.

In some of these embodiments, wherein L is a bond or -CH ₂ -, R ₁ is cyclobutyl, and Ring A is

In another embodiment, the present invention includes compounds of formula (I), wherein:

L is a bond or –CH ₂ –;

R ₁ is tert-butyl or cyclobutyl;

R is optionally substituted phenyl or optionally substituted ₆ -membered heteroaryl;

Wherein the substitution of phenyl or 6-membered heteroaryl is selected from:

Hydroxy, fluoro, methoxy, cyano, amino, -C(=O)-NH ₂ and pentafluoro-λ～6～-sulfanyl;

Ring A is

and

R ₃ is H or cyano.

In another embodiment, the present invention includes compounds of formula (I), wherein:

L is a bond or –CH ₂ –;

R ₁ is tert-butyl or cyclobutyl;

_R is optionally substituted phenyl, optionally substituted pyridine, or optionally substituted pyrimidine;

Wherein the substitution of phenyl, pyridine or pyrimidine is selected from:

Hydroxy, fluoro, methoxy, cyano, amino, -C(=O)-NH ₂ and pentafluoro-λ~6~-sulfanyl; and

Ring A is

Embodiments of the present invention also include optical isomers, hydrates, metabolites, enantiomers, diastereomers, cis-trans isomers, racemates, prodrugs or pharmaceutically acceptable salts thereof.

One embodiment of the present invention provides a compound selected from the compounds listed in Table 1.

Table 1

Specifically, one embodiment of the invention comprises a compound selected from the compounds listed in Table 2.

Table 2

One embodiment of the invention provides a compound selected from the compounds listed in Table 1A.

Table 1A

Another embodiment of the present invention provides a compound selected from the compounds listed in Table 1, Table 2 and 1A.

The present invention also relates to pharmaceutical compositions comprising, but not limited to, one or more of the compounds disclosed herein and a pharmaceutically acceptable carrier or excipient.

Another embodiment of the invention is a pharmaceutical composition of the invention comprising at least one compound selected from the compounds listed in Table 1 . Another embodiment of the invention is a pharmaceutical composition of the invention comprising at least one compound selected from the compounds listed in Table 3.

Specifically, an embodiment of the present invention is a pharmaceutical composition of the present invention comprising at least one compound selected from the compounds listed in Table 2.

The invention also features a method of treating a subject having or being diagnosed with a disease and/or disorder mediated by FLAP activity, the method comprising administering to the subject a therapeutically effective amount of at least one formula (I) compound of.

The invention also features methods for preventing, treating, ameliorating (including but not limited to inhibiting) the progression of FLAP-mediated diseases and/or disorders in a subject in need thereof, the method comprising adding The subject is administered a therapeutically effective amount of at least one compound of formula (I). Such diseases and/or disorders include, but are not limited to, diabetes, respiratory disorders, and their related symptoms or complications. More particularly, the present invention relates to the treatment of, but not limited to, exacerbated, non-allergic asthma, fibrotic lung disease, acute respiratory distress syndrome and chronic obstructive pulmonary disease and their use in subjects with such diseases and/or disorders Methods for related symptoms or complications.

In another embodiment, the compounds of the present invention are useful for ameliorating symptoms associated with and/or treating the following cardiac and cardiovascular diseases and/or disorders: myocardial infarction, atherosclerosis , atherosclerosis and stroke aortic aneurysm or their associated symptoms or complications in subjects with such diseases and/or disorders.

In another embodiment, the compounds of the present invention are useful for ameliorating symptoms and/or treating autoimmune or allergic diseases and/or disorders associated with autoimmune or allergic diseases and/or disorders, wherein said autoimmune or allergic Diseases and/or disorders include, but are not limited to, rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty exudates, systemic lupus erythematosus, systemic sclerosis, Alzheimer's disease, multiple sclerosis, allergic rhinitis, allergic dermatitis and asthma or their associated symptoms or complications in subjects with such diseases and/or disorders.

In another embodiment, the compound of the present invention can be used to improve the symptoms and/or prevent or treat carcinogenesis, including but not limited to tumor cell proliferation, differentiation, apoptosis, tumor-associated angiogenesis and cancer Cell migration and invasion.

Another embodiment of the present invention provides a process for the preparation of a pharmaceutical composition comprising admixing any one of the compounds according to formula (I) with a pharmaceutically acceptable carrier.

In yet another embodiment of the invention, a method for treating or ameliorating a FLAP-mediated disease and/or disorder in a subject in need thereof comprises administering to the subject a therapeutically effective amount of at least one formula ( I), wherein the therapeutically effective amount of the compound of formula (I) is about 0.1 mg/dose to about 5 g/dose. Specifically, a therapeutically effective amount of a compound of formula (I) is from about 0.5 mg/dose to about 1000 mg/dose.

More specifically, a therapeutically effective amount of a compound of formula (I) is from about 1 mg/dose to about 100 mg/dose. In yet another embodiment of the present invention, the daily dosage of the compound of formula (I) is 1 to 3 dosages. In yet another embodiment of the present invention, the therapeutically effective amount of the compound of formula (I) is from about 0.001 mg/kg/day to about 30 mg/kg/day. More specifically, a therapeutically effective amount of a compound of formula (I) is from about 0.01 mg/kg/day to about 2 mg/kg/day.

The present invention will be further described below.

A) Terminology

Some terms are defined below and used throughout this disclosure.

It should also be noted that any atom with an unsaturated valence in the text, schemes, examples, formulas and any tables herein is assumed to have one or more hydrogen atoms which saturate the valence.

As used herein, the following terms are intended to have the following definitions. Definitions herein may state that a chemical term has a given chemical formula. The particular formulas given are not intended to limit the scope of the invention, but are used merely to illustrate the terminology. The scope of the definitions themselves is intended to include variations that would be expected to be included by one of ordinary skill in the art.

The term "C _1-n alkyl" means a saturated branched or straight chain hydrocarbon group having 1 up to n carbon atoms arranged in a straight or branched chain, where n is 4 or 5. Examples include methyl, ethyl, 1-propyl, 2-propyl, isobutyl, tert-butyl, isopentyl, neopentyl, pent-3-yl, etc., and all of those illustrated in the following examples . The alkyl group can be attached to the core molecule through any atom as permitted by the available valences.

The term "C _3-6 cycloalkyl" means a saturated or partially unsaturated monocyclic hydrocarbon ring system group. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and all exemplified in the examples below. A C _3-5 cycloalkyl group can be attached to the core molecule through any ring atom as permitted by available valences.

The term "aryl" means an unsaturated aromatic monocyclic or polycyclic hydrocarbon ring system group. Examples include phenyl, etc., and all are exemplified in the following examples. The aryl group can be attached to the core molecule through any ring atom as permitted by available valences.

When used as a prefix to a ring system, the term "hetero" means that at least one carbon atom ring member in the ring system is replaced by a heteroatom selected from N, O, S, S(O ₎ or SO2. A heterocyclic ring can have 1, 2, 3 or 4 carbon atom ring members replaced by nitrogen atoms. Alternatively, the ring may have 1, 2 or 3 nitrogen atom ring members and 1 oxygen or sulfur atom ring member. Alternatively, the ring may have 1 oxygen or sulfur atom ring member. Alternatively, up to two adjacent ring members may be heteroatoms, one of which is nitrogen and the other heteroatom is selected from N, S or O.

The term "heteroaryl" means an unsaturated monocyclic, polycyclic aromatic "hetero" ring system group selected from: pyrazolyl, Diazolyl, furyl, imidazolyl, imidazolidinyl, triazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, benzimidazolyl, benzo Azolyl, quinoxalinyl, quinazolinyl, benzothiazolyl, iso Azolyl, thiazolyl, Azolyl, thiazolopyridyl, thienopyrimidinyl and isoindolyl. Examples include 1H-pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-5-yl, 1,2,4- Oxadiazol-5-yl, 1,2,4- Oxadiazol-3-yl, furan-2-yl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, imidazolidine-1- Base, 1H-1,2,4-triazol-1-yl, 1H-1,2,4-triazol-2-yl, 1H-1,2,4-triazol-3-yl, 1H-1 ,2,4-triazol-4-yl, 1H-1,2,3-triazol-1-yl, 2H-1,2,3-triazol-2-yl, pyridin-3-yl, pyrimidine- 1-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridazin-2-yl, pyridazin-3-yl, pyridazin-4-yl, pyrazin-1-yl, Pyrazin-2-yl, pyrazin-3-yl, benzimidazol-1-yl, benzo Azol-2-yl, quinoxalin-2-yl, quinazolin-2-yl, benzothiazol-2-yl, iso Azol-3-yl, 1,3-thiazol-4-yl, 1,3- Azol-2-yl, isoindol-1-yl, thiazolo[4,5-b]pyridinyl, thieno[2,3-d]pyrimidinyl, etc., and all exemplified in the examples below. A heteroaryl group can be attached to the core molecule through any ring atom as permitted by available valences.

The term "heterocyclyl" means a saturated monocyclic "hetero" ring system radical selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl and tetrahydro-2H-pyranyl. Examples include azetidin-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl Base, piperidin-4-yl, piperazin-1-yl, tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, tetrahydro-2H-pyran-4-yl, etc. etc., and all exemplified in the example below. A heterocyclyl group can be attached to the core molecule through any ring atom as permitted by available valences.

The term "carboxy" means a group represented by the formula: -C(O)OH.

The term "halogen" or "halo" means a group selected from chloro, bromo, fluoro or iodo.

The term "oxo" means a group represented by the formula: =0.

The term "substituted" refers to a group wherein one or more hydrogen atoms are each independently replaced by the same or different substituents. In preferred embodiments, each independently replaces up to 3 hydrogen atoms.

With respect to substituents, the term "independently" means that where there may be more than one such substituent, these substituents may be the same or different from each other.

The definition of any substituent or variable at a particular position in a molecule is not intended to be independent of its definition elsewhere in the molecule. It is understood that the substituents and substitution patterns on the compounds of the present invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and readily synthesized by techniques known in the art and those shown herein.

In general, IUPAC naming conventions are used in this paper unless otherwise specified.

For quantitative expressions given herein, whether or not the term "about" is explicitly used, it is meant that each quantity given herein is qualified by that term, or that both the actual given value and the value generally indicated in the art Approximations to these given values will be made that can be reasonably reasoned by the art, including approximations to these given values that result from experimental and/or measurement conditions.

The term "form" means a compound of the present invention which is available as, but not limited to, salt, stereoisomer, tautomer, crystal, polymorph, amorphous, solvate, hydrate, ester, pro drug or metabolite form. The present invention covers all these compound forms as well as mixtures thereof.

When referring to a compound of the present invention, the term "isolated form" means a state in which it can be substantially purified, such as, but not limited to, enantiomers, racemic mixtures, geometric isomers (such as cis or trans stereoisomers) isomers), mixtures of geometric isomers, etc. exist. The present invention covers all these compound forms as well as mixtures thereof.

The term "composition" is intended to cover a product comprising the specified ingredients in the specified amounts as well as any product resulting, directly or indirectly, from the combination of the specified ingredients in the specified amounts.

As used herein, the term "subject" refers to a patient, such as an animal, mammal or human, who is the subject of treatment, observation or experimentation and is at risk of developing (or susceptible to) a FLAP-mediated disorder .

The term "administration" also means that the individual components to be combined may be administered as one formulation or as different formulations at the same or different times during the treatment cycle. Accordingly, the invention is to be understood as encompassing any and all modes of administration, at the same time or at different times. The scope of combinations of the compounds of the present invention with other therapeutic agents useful for the aforementioned disorders covers in principle all combinations of the compounds of the present invention with all therapeutic agents useful for the aforementioned disorders.

The term "treating" refers, without limitation, to promoting the elimination, preventing, ameliorating or otherwise inhibiting the progression of, or promoting the arrest of, FLAP-mediated diseases and/or disorders or their associated symptoms or complications.

The term "prodrug" means a form of a compound of formula (I) or its in vivo transformation into a functional derivative that can contribute to therapeutic biological activity, wherein the transformation form can be: 1) a relatively active form; 2) a relatively non-active form. active form; 3) a relatively low activity form or 4) any form resulting directly or indirectly from such in vivo transformation. Prodrugs are useful in any case where the compound is too toxic to be administered systemically, is insufficiently absorbed from the digestive tract, or is broken down by the body before it reaches the target. General methods for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs ", edited by H. Bundgaard, Elsevier, 1985.

The term "metabolite" means a prodrug form of a compound of formula (I) or a form thereof which is converted by in vivo metabolism or metabolic processes into a relatively low activity functional derivative of said compound.

The term "medicament" or "medicament" refers to a product containing a compound of formula (I) or a form thereof. The invention includes the use of such agents to treat FLAP-mediated disorders.

The term "in combination" refers to the use of a combination product comprising a compound of formula (I) or a pharmaceutical composition, medicament or medicament form thereof and at least one therapeutic agent for the treatment of FLAP-mediated disorders.

Methods for determining effective dosages for therapeutic and prophylactic purposes of the disclosed pharmaceutical compositions or the disclosed pharmaceutical combinations, whether formulated in the same composition or not, are known in the art.

For therapeutic purposes, as used herein, the term "therapeutically effective amount" or "effective amount" means, alone or in combination, eliciting in a tissue system, animal, or human the biological or medical effect that the researcher, veterinarian, physician, or other clinician is seeking. The amount of each active compound or agent that responds, including alleviation of symptoms of the disease and/or disorder being treated. For prophylactic purposes (i.e., to inhibit the progression of the disorder), the term "therapeutically effective amount" refers to each of these, alone or in combination, that treats or inhibits the progression of the disorder in a subject as sought by the researcher, veterinarian, physician, or other clinician. The amount of active compound or agent. Thus, the invention provides a combination of two or more drugs, wherein for example (a) each drug is administered in an independently therapeutically or prophylactically effective amount; (b) at least one drug in the combination, if administered alone, is administered in an amount administered in less than therapeutic or less than prophylactic amounts, but which are therapeutic or prophylactic when administered in combination with a second or additional drug according to the invention; or (c) if administered alone, both (or more Multiple) drugs are administered in less than therapeutic or less than prophylactic amounts, but are therapeutic or prophylactic when administered together. An effective amount of the compound is from about 0.001 mg/kg/day to about 300 mg/kg/day.

Advantageously, for the treatment of a FLAP-mediated disease and/or disorder or its associated symptoms or complications compared to an effective amount of the compound or therapeutic agent recommended for the treatment of the disease and/or disorder or its associated symptoms or complications An effective amount of a combination product for a disease may be a reduced amount of the compounds and/or therapeutic agents. Thus, it is contemplated that the compound is administered before, during, or after the time of administration of the agent.

The term "pharmaceutically acceptable salt" refers to a non-toxic pharmaceutically acceptable salt (see Int'l J.Pharm., 1986, 33:201-217; J.Pharm.Sci., 1997 (Jan), 66 (1): 1). However, other salts known to those skilled in the art may also be used in the preparation of the compounds according to the invention or their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, Malic acid, malic acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, isethanoic acid, benzenesulfonic acid, oxalic acid, pamoic acid, 2-naphthalenesulfonic acid, p-toluenesulfonic acid, cyclohexaneamino Sulfonic Acid, Salicylic Acid, Saccharic Acid, or Trifluoroacetic Acid. Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, Lithium, Magnesium, Potassium, Sodium and Zinc.

The compounds of the present invention may exist in the form of pharmaceutically acceptable salts. For pharmaceutical use, "pharmaceutically acceptable salts" of compounds of the present invention refer to non-toxic acidic/anionic or basic/cationic salt forms.

Suitable salt forms include acid addition salts which can be obtained, for example, by reacting a solution of a compound according to the invention with a compound such as acetic acid, adipic acid, benzoic acid, carbonic acid, citric acid, fumaric acid, glycolic acid, hydrochloric acid, maleic acid, etc. , malonic acid, phosphoric acid, saccharic acid, succinic acid, sulfuric acid, tartaric acid, trifluoroacetic acid, etc.

In addition, if the compound of the present invention bears an acidic moiety, suitable salts thereof may include alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; and salts with suitable organic ligands. , such as quaternary ammonium salts.

During any of the methods used to prepare the compounds of the invention, it may be necessary and/or desirable to protect sensitive or reactive groups in any molecule concerned. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, JFW McOmie eds., Plenum Press, 1973 and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, 1999. Protecting groups can be removed at a convenient subsequent stage by methods known in the art. The scope of the invention covers all protected compound forms as well as mixtures thereof.

The present invention includes various isomeric compounds and mixtures thereof. The term "isomer" refers to compounds having the same composition and molecular weight but differing in physical and/or chemical properties. Such substances have the same number and kind of atoms, but different structures. Structural differences may lie in conformation (geometric isomers) or in the ability to rotate the plane of polarized light (optical isomers).

The term "stereoisomer" refers to isomers having the same molecular formula and the same sequence of covalently bonded atoms, but different orientations in space.

The term "optical isomer" means isomers that are identical in structure but differ only in the spatial arrangement of their groups. Optical isomers rotate the plane of polarized light in different directions. The term "optical rotation" means the degree to which an optical isomer rotates the plane of polarized light.

The terms "racemate" or "racemate" mean an equimolar mixture of two enantiomeric species, wherein each separated species rotates the plane of polarized light in opposite directions, rendering the mixture optically inactive .

The term "enantiomer" means an isomer having a non-superimposable mirror image. The term "diastereomers" means stereoisomers that are not enantiomers.

The term "chiral" means a molecule that, when in a given configuration, cannot be superimposed onto its mirror image. This is in contrast to achiral molecules, which can be superimposed to their mirror images.

Depending on how the polarized light is rotated, these two distinct mirror image forms of chiral molecules are also called levorotatory (rotated to the left), abbreviated L, or dextrorotatory (rotated to the right), abbreviated d. The symbols "R" and "S" represent the configuration of the group around the stereocarbon atom.

The term "geometric isomer" means isomers that differ in the orientation of substituent atoms with respect to carbon-carbon double bonds, cycloalkyl rings, or bridged bicyclic ring systems. According to the Cahn-Ingold-Prelog priority rules, the substituent atoms (other than hydrogen) on both sides of the carbon-carbon double bond can be in the E configuration or the Z configuration. In the "E" configuration, the substituent with the highest priority is on the opposite side to the carbon-carbon double bond. In the "Z" configuration, the substituents with the highest priority are oriented on the same side relative to the carbon-carbon double bond.

A substituent atom (other than hydrogen) attached to a ring system may be in the "cis" or "trans" configuration. In the "cis" configuration, the substituents are on the same side relative to the plane of the ring; in the "trans" configuration, the substituents are on opposite sides relative to the plane of the ring. Compounds that have a mixture of "cis" and "trans" species are called "cis/trans species".

Isomer descriptors ("R", "S", "E" and "Z") indicate the configuration of atoms and are intended to apply as defined herein.

Individual isomers of the compounds of the invention may be prepared by isomer-specific synthesis or by resolution from isomeric mixtures. Conventional resolution techniques involve combining an optically active acid (or base) with the free base (or free acid) of each isomer of the isomer pair to form an optically active salt (followed by fractional crystallization and regeneration of the free base), by Reaction with an appropriate chiral auxiliary to form the ester or amide of each isomer of the isomeric pair (subsequent fractional crystallization or chromatographic separation and removal of the chiral auxiliary) or the intermediate or The isomeric mixture of the final product was separated.

Furthermore, the compounds of the present invention may have one or more polymorphic or amorphous crystalline forms and are thus intended to be encompassed within the scope of the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or with common organic solvents (eg, organic esters, eg, alcoholates, etc.), and these are also intended to be encompassed within the scope of this invention.

B) compound

Representative compounds of the invention are listed in Table 3 below.

table 3

C) synthesis

The present invention provides methods for preparing the disclosed compounds according to conventional methods of organic synthesis as well as matrix or combinatorial methods of synthesis. Scheme A describes the proposed synthetic route. Using the following schemes, guidance, and examples, one of skill in the art can develop analogous or analogous methods for a given compound within the present invention. These methods are representative of synthetic schemes and should not be construed as limiting the scope of the invention.

When the compounds according to the invention possess at least one chiral center, they can exist correspondingly as enantiomers. If compounds possess two or more chiral centers, they may also exist as diastereomers. If the processes used to prepare the compounds according to the invention result in mixtures of stereoisomers, these can be separated by conventional techniques such as preparative chromatography. Compounds may be prepared in racemic form either by stereospecific synthesis or by resolution as individual enantiomers or diastereomers. A compound can be resolved, for example, into its component enantiomers or diastereomers by standard techniques, for example by formation of a salt with an optically active base to form stereoisomer pairs, followed by fractional crystallization and regeneration of the free acid. Compounds can also be resolved by formation of stereoisomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved on a chiral HPLC column. It is to be understood that all stereoisomers, racemic mixtures, diastereomers, geometric isomers and their enantiomers are encompassed within the scope of the present invention.

Representative compounds of the invention can be synthesized according to the general synthetic schemes described below and more particularly illustrated in the specific synthetic examples that follow. The general schemes are given by way of illustration; the invention should not be construed as being limited by the chemical reactions and conditions shown. Methods for the preparation of various starting materials used in the Schemes and Examples are well known to those skilled in the art. No attempt was made to optimize the yields obtained in any of the exemplified reactions. Those skilled in the art will know how to increase such yields by routine changes in reaction times, temperatures, solvents and/or reagents.

General protocol: ¹ H and ¹³ CNMR spectra were measured on a Bruker AC-300 (300 MHz) spectrometer using tetramethylsilane and deuterated solvent as internal standards, respectively. Elemental analyzes were obtained by Quantitative Technologies Inc. (Whitehouse, New Jersey) and results were within 0.4% of calculated values unless otherwise stated. Melting points were determined in an open-tube capillary with a Mel-TempII apparatus (Laboratory Devices Inc.) and were uncorrected. Electrospray mass spectra (MS-ESI) were recorded in positive ion mode on a Hewlett Packard 59987A spectrometer. High-resolution mass spectra (HRMS) were obtained using fast atom bombardment (FAB) technique on a MicromassAutospec.E spectrometer.

Furthermore, certain crystalline forms of the compounds may exist as polymorphs and are thus also intended to be encompassed by the present invention. In addition, some of the compounds may form solvates with water (ie, hydrates) or with common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

Examples of such synthetic routes include Scheme A, Intermediates A-N, Examples 1-351 and Hypothetical Examples 1-36. Compounds similar to the object compounds of these examples can be prepared by similar routes. The disclosed compounds are useful as medicaments as described herein.

Abbreviations or acronyms used herein include:

general guidance

Representative compounds of the invention can be synthesized according to the general synthetic methods described below and shown more particularly in the schemes that follow. Since the schemes are illustrative, the invention should not be construed as limited to the chemical reactions and conditions shown. The preparation of the various starting materials used in the schemes is well within the skill of those in the art. Substituents for compounds of formula (I) or forms thereof shown in the following schemes are as previously defined herein.

The reaction solutions were stirred at room temperature under an atmosphere of N2 _(g) or Ar _(g) unless otherwise indicated. When the solution is "concentrated to dryness", it is concentrated under reduced pressure using a rotary evaporator, and when the solution is dried, it is usually dried with a desiccant such as magnesium sulfate (MgSO ₄ ) or sodium sulfate (Na ₂ SO ₄ ).

Ethyl acetate (EtOAc)/hexanes, _CH2Cl2 /MeOH, _CH2Cl2 / ₁₀ % _2NNH3 in MeOH, _CH2Cl2 /i _- PrOH, etc. _were used as eluents unless otherwise indicated, use Silica gel column Normal phase flash column chromatography (FCC) was performed on silica gel.

Reversed-phase high-performance liquid chromatography (HPLC) was carried out under the following conditions: 1) Instrument: Shimadzu; Chromatographic column: WatersXBridgeC18 10μM (250×50mm), Phenomenex Gemini chromatographic column 5μmC18 (150×21.2mm) or WatersXterraRP18OBD5μm (100×30mm); Gradient: 95:5 to 0:100 water (0.05% trifluoroacetic acid (TFA))/CH ₃ CN (0.05% TFA); flow rate: 30-80mL/min; detection: UV light at λ=220-254nM; 2) Instrument: Gilson; Chromatographic column: Phenomenex LUNA chromatographic column 5μmC18 (250×50mm) or WatersXBridgePrepC18OBD5μm (30×150mm); Gradient: 95:5 to 0:100 water (0.05% TFA)/CH ₃ CN (0.05% TFA) ; Flow rate: 30-80mL/min; Detection: UV light under λ=220-254nM; 3) Instrument: Gilson/Shimadzu; , 5 μm); gradient: water-acetonitrile (both phases have 0.05 vol% trifluoroacetic acid); hold at 5% ACN for 1 min, then ramp up to 99% ACN in 6 min, then hold at this concentration for 3 min. Flow rate: 80 mL/min; chromatographic column heated at 46° C., detected with UV light at λ=254 nm; and 4) Instruments: Dionex: UVD170U diode array detector and ThermoFinnegan Surveyor MSQplus mass spectrometer for data collection. WatersXBridgeC185μMOBD50×100mm preparative column. All runs were with water-acetonitrile with 20 mM NH ₄ OH added to the aqueous phase and all gradients had a flow rate of 80 mL/min using the following four possible gradients: 1) 50% MeCN to 60% MeCN in 12 min , then increased to 100% MeCN and maintained for 6.3min; 2) increased from 30% MeCN to 70% MeCN within 12min, then increased to 100% MeCN and maintained for 6.3min; 3) increased from 50% MeCN to 80% within 12min % MeCN, then ramped to 100% MeCN and held for 6.3 min; and 4) ramped from 60% MeCN to 100% MeCN over 12 min, then held for 6.3 min. The total run time for all gradient systems was 18.5 min.

In the example where the solution was filtered through a syringe filter, Pall 0.45 μM GHP membrane 13 mm and 25 mm diameter syringe filters were used.

Thin-layer chromatography was performed using Merck silica gel 60F ₂₅₄ 2.5 cm × 7.5 cm 250 μm or 5.0 cm × 10.0 cm 250 μm pre-coated silica gel plates. Preparative thin layer chromatography was performed using EM Science silica gel 60F ₂₅₄ 20 cm x 20 cm 0.5 mm precoated plates with a 20 cm x 4 cm concentrated zone. Microwave reactions were performed at the indicated temperatures in a CEM Discover beta or BiotageInitiator ^™ or Optimizer ^™ microwave. Mass spectra were acquired on an Agilentseries 1100 MSD using electrospray ionization (ESI) in positive ion mode unless otherwise indicated. The calculated mass corresponds to the exact mass. NMR spectra were obtained on a Bruker model DPX400 (400 MHz), DPX500 (500 MHz) or DRX600 (600 MHz) spectrometer. The format of the ¹ H NMR data below is: downfield chemical shift (in ppm) referenced to tetramethylsilane (multiplicity, coupling constant J in Hz, integration).

HCl (4N di solution in _Et20 or 1.25N in MeOH) and the mixture was concentrated to obtain the HCl salt, or the resulting solid was isolated by filtration to obtain the hydrochloride salt. The trifluoroacetate salt was obtained by purifying the crude reaction product by preparative reverse phase HPLC, whereby the final product was isolated as monofluoroacetate, difluoroacetate or trifluoroacetate.

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoft Corp., Cambridge, MA) or ACD/Name Version 10.01 (Advanced Chemistry).

Compounds of formula (I) wherein rings A, L, R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are as defined in formula (I) can be summarized by the general synthetic route shown in Scheme A to synthesize.

Referring to Scheme A, compounds of formula (XIII) can be prepared from appropriately substituted phenols (X) wherein the phenols (-OP) are protected as alkyl or alkyl and aryl silyl ethers. Phenols protected as methyl ethers can be prepared by known methods or are commercially available. Compounds (X) where W is hydrogen and X is bromo or chloro can be used such as LDA and lithium tetramethylpiperidinium (LTMP) (prepared in situ or obtained from commercial sources) and triisopropylboronic acid The base of the salt is converted to the corresponding boronic acid (XIV) by directional ortho metalation (DOM) in solvents such as THF, DME, ether, and mixtures thereof at temperatures in the range ^of -78-0°C. In compounds of formula (XIV) where X is bromo or chloro and Z is fluoro or hydrogen, compound (XV) can be obtained by sequential Pd cross-coupling reactions to load Ar ¹ followed by Y . Preferred solvents for cross-coupling reactions are solvents such as DME, DMSO, DMF, DMA, di alkane, THF, EtOH or toluene or a mixture of the above solvents (with or without added water), in the presence of such as Na ₂ CO ₃ , K ₂ CO ₃ , KOAc, KH ₂ PO ₄ , K ₂ HPO ₄ or K ₃ In the case of a base of PO ₄ , such as Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ , palladium(II) trifluoroacetate and Ph ₃ P, chloro(2-dicyclohexylphosphine-2',4',6 '-Triisopropyl-1,1'-diphenyl)[2-(2-aminoethyl)phenyl)]-palladium(II), 1,1'-bis[di-tert-butylphosphine]di A palladium catalyst of ferrocene]-palladium(II) chloride, the reaction is carried out at a temperature ranging from room temperature to 120°C.

Furthermore, compounds of formula (XI) wherein W is hydrogen, Z is H or fluoro and Y is alkyl or cycloalkyl can be formed from compounds (X) wherein X is bromo by using methods such as nBuLi or i-PrMgCl with alkyllithium or alkylmagnesium halide reagents in solvents such as diethyl ether or THF at temperatures ranging ^from −78 °C to room temperature followed by treatment with an electrophile. In cases where a ketone such as cyclobutanone or cyclopentanone is used as the electrophile, the resulting hydroxyl group can be reduced using known methods, such as _Et3SiH in DCM in the presence of TFA. Alternatively, compounds of formula (XI) can be obtained by using a palladium catalyst such as palladium(II) acetate (with added complex (X) to an alkyl or aryl zinc reagent such as cyclobutyl Zinc bromide. Compounds of formula (XI) can be further synthesized into those of formula (XII) using methods previously described such as DOM, borylation and Pd-mediated cross-coupling. Compounds of formula (X) wherein X is alkyl, aryl or heteroaryl can be converted to compounds of formula (XII) or (XV) by using methods such as DOM, borylation and Pd-mediated cross-coupling.

Compounds of formula (XIII) can be obtained from those of formula (XII) or (XV) by first removing the silyl protecting group using a fluoride source such as TBAF or CsF in a solvent such as THF, Then in the presence _of a suitable electrophile and a solvent such as DMF, DMSO and DMA, in the _{presence of} a base such as _K2CO3 , _Cs2CO3 , _{Na2CO3 and K2PO4} , in The resulting phenol is subjected to S _N 2 or S _N Ar reaction conditions at a temperature in the range of 0-140 °C. Alternatively, compounds of formula (XIII) may be prepared via intermediates of formula (XII) and (XV), wherein P is a methyl group. Methyl groups can be removed using known methods. A preferred method of removing methyl ether involves using _BBr3 in DCM at a temperature in the range ^of -78°C to 0°C. Compounds of formula (XIII) are suitable electrophiles using such as various alkyl, aryl and heteroaryl halides, in the presence _of a base such as K2CO3 or _{Cs2CO3 (} with or without a cation chelating agent ₎ , such as in the case of 18-crown-6), by conventional heating or microwave heating in solvents such as DMSO, DMA, ACN, DMF, and mixtures thereof, at temperatures in the range of 0-140°C.

Option A

example

The following examples are given by way of illustration; the invention should not be construed as being limited by the chemical reactions and conditions shown.

Intermediate A

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

Step A: 1-(3-fluoro-2-methoxyphenyl)cyclobutanol.

To a 500 mL round bottom flask was added a stir bar, 2-bromo-6-fluoroanisole (11.03 g, 53.8 mmol) and anhydrous THF (215 mL). The flask was purged with nitrogen and cooled to 0 °C, then 2.0 Mi-PrMgCl in THF (60 mL, 120 mmol) was added within 3 min. The resulting mixture was stirred for 2 h, then cyclobutanone (5.0 mL, 67 mmol) was added. The resulting mixture was stirred for 0.5 h, then diluted with _Et2O (500 mL), and washed with saturated _NH4Cl , then brine. The organic layer was separated, dried over _MgSO4 , filtered and concentrated to dryness to give a pale yellow oil. The residue was subjected to FCC to yield 1-(3-fluoro-2-methoxyphenyl)cyclobutanol (5.18 g, 49%) as a pale yellow oil. ¹ HNMR (600MHz, CDCl ₃ ) δ7.07–7.03 (m, 1H), 7.03–6.98 (m, 1H), 6.98–6.94 (m, 1H), 3.99 (d, J=2.4, 3H), 3.39 ( s,1H), 2.57–2.45(m,2H), 2.41–2.31(m,2H), 2.17–2.05(m,1H), 1.75–1.65(m,1H).

Step B: 1-cyclobutyl-3-fluoro-2-methoxybenzene.

To a 500 mL round bottom flask was added a stir bar, 1-(3-fluoro-2-methoxyphenyl)cyclobutanol (5.21 g, 26.6 mmol), anhydrous DCM (250 mL), _EtSiH (39.0 mL, 244mmol) and TFA (20mL, 260mmol). The resulting mixture was stirred at room temperature for 22 h, then concentrated to dryness, and the residue was subjected to FCC to give 1-cyclobutyl-3-fluoro-2-methoxybenzene (3.78 g, 79%) as a pale yellow oil. ¹ HNMR (600MHz, CDCl ₃ ) δ7.03–6.99 (m, 1H), 6.99–6.95 (m, 1H), 6.91 (m, 1H), 3.86 (d, J=1.6, 3H), 3.83–3.72 ( m,1H), 2.39–2.28(m,2H), 2.19–2.07(m,2H), 2.07–1.98(m,1H), 1.89–1.80(m,1H).

Step C: (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid.

To a 500 mL round bottom flask was added a stir bar, anhydrous THF (60 mL) and 2,2,6,6-tetramethylpiperidine (8.0 mL, 47 mmol). The flask was cooled to -78°C (bath temperature) and then treated with 2.5M n-BuLi in hexane (18.0 mL, 45 mmol) for 2 min. The resulting mixture was stirred for 5 min, then allowed to warm to 0 °C. After 35 min, the mixture was recooled to -78 °C and treated with B(O-iPr) ₃ (10.20 mL, 44 mmol) for 4 min. After 16 min, a solution consisting of 1-cyclobutyl-3-fluoro-2-methoxybenzene (7.24 g, 40.2 mmol) and anhydrous THF (20.0 mL) was added within 6 min, stirring was continued for 3.5 h, then HOAc (8 mL). The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL), the extract was dried over MgSO, filtered and concentrated to dryness to afford ( ₄ -cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid ( 8.08g, 90%). The crude product was used directly in the next synthetic step.

Step D: 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine .

A stir bar, 2-amino-5-bromopyrazine (19.95 g, 115.3 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (25.0 g , 112 mmol), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (5.92 g, 7.28 mmol) and K ₂ CO ₃ (47.33 g, 343 mmol). The flask was purged with nitrogen and filled with sparged toluene (97 mL), sparged water (97 mL) and sparged DMF (61 mL). The reaction vessel was heated at 80°C for 17 hours and then cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was extracted with EtOAc (200 mL x 3), the combined extracts were dried over MgSO ₄ , filtered and concentrated to dryness. The residue was subjected to FCC to give the title compound (29.68g). MS (ESI): mass calculated for _C15H16FN3O : _273.13 ; _m /z found: 274.1 [M+H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.32–8.26 (dd, J=2.5,1.5,1H), 8.02–7.96 (d, J=1.5,1H), 7.54–7.47 (m,1H), 7.20 –7.14(m,1H),6.65(s,2H),3.87–3.79(d,J＝1.0,3H),3.79–3.68(m,1H),2.34–2.24(m,2H),2.17–2.06( m,2H), 2.06–1.94(m,1H), 1.87–1.76(m,1H).

Intermediate B

3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol

Method 1 :

Step A: 1-(3-fluoro-2-methoxyphenyl)cyclobutanol .

To a 3 L round bottom flask was added a stir bar, 2-bromo-6-fluoroanisole (75.00 g, 370 mmol) and anhydrous THF (1460 mL). The flask was purged with nitrogen and cooled to 0 °C, then 2.0 Mi-PrMgCl in THF (408 mL, 916 mmol) was added within 15 min. The resulting mixture was stirred for 2 hours, then cyclobutanone (34 mL, 455 mmol) was added. The resulting mixture was stirred for 0.5 h, then diluted with _Et2O (2.50 L), and washed with saturated _NH4Cl , then brine. The organic layer was separated, dried over _MgSO4 , filtered and concentrated to dryness to give crude product. The residue was subjected to FCC to give the title compound (55.58 g). ¹ HNMR (400MHz, CDCl ₃ )δ6.98-6.88(m,3H),3.90-3.90(s,3H),2.46–2.42(m,2H),2.31–2.28(m,2H),2.04(m, 1H), 1.67–1.64 (m, 1H).

Step B: 1-cyclobutyl-3-fluoro-2-methoxybenzene .

To a 3 L round bottom flask was added a stir bar, 1-(3-fluoro-2-methoxyphenyl)-cyclobutanol (80.17 g, 410 mmol), anhydrous DCM (1231 mL), Et ₃ SiH (200 mL, 1.23 mol) and TFA (93 mL, 1.2 mmol). The resulting mixture was stirred at room temperature for 22 h, then concentrated to dryness, and the residue was subjected to FCC to give 1-cyclobutyl-3-fluoro-2-methoxybenzene (51.90 g, 70.5%) as a pale yellow oil. ¹ HNMR (400MHz, CDCl ₃ )δ7.07–6.93(m,3H),3.91(s,3H),3.85–3.81(m,1H),2.40–2.36(m,2H),2.20–2.07(m, 3H), 1.91–1.88 (m, 1H).

Step C: (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid .

To a 500 mL round bottom flask was added a stir bar, anhydrous THF (83 mL) and 2,2,6,6-tetramethylpiperidine (11 mL, 65 mmol). The flask was cooled to -78 °C (bath temperature) and then treated with 2.5M n-BuLi in hexane (25 mL, 62.5 mmol) for 2 min. The resulting mixture was stirred for 5 min, then allowed to warm to 0 °C. After 35 min, the mixture was recooled to -78 °C and treated with B(O-iPr) ₃ (14 mL, 60 mmol) for 4 min. After 16 min, a solution consisting of 1-cyclobutyl-3-fluoro-2-methoxybenzene (10.0 g, 55.6 mmol) and anhydrous THF (27 mL) was added over 6 min, stirring was continued for 3.5 h, then saturated _NH4Cl (200 mL). The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL x 3), the combined extracts were dried over MgSO ₄ , filtered and concentrated to dryness to give the crude product as an off-white solid. The crude product was subjected to FCC to afford the title compound (7.21 g). ¹ HNMR (400MHz, CD ₃ OD): δ7.11-7.07 (m, 2H), 3.38 (s, 3H), 3.82-3.80 (m, 1H), 2.37-2.33 (m, 2H), 2.19-2.11 ( m,3H), 2.09-1.90(m,1H).

Step D: 5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine .

A stir bar, 2-amino-5-bromopyrazine (19.95 g, 115.3 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (25.0 g , 112 mmol), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (5.92 g, 7.28 mmol) and K ₂ CO ₃ (47.33 g, 343 mmol). The flask was purged with nitrogen and filled with sparged toluene (97 mL), sparged water (97 mL) and sparged DMF (61 mL). The reaction vessel was heated at 80°C for 17 hours and then cooled to room temperature. The reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was extracted with EtOAc (200 mL x 3), the combined extracts were dried over MgSO ₄ , filtered and concentrated to dryness. The residue was subjected to FCC to give the title compound (29.68g). MS (ESI): mass calculated for _C15H16FN3O : _273.13 ; _m /z found: 273.9 [M+H] ⁺ .

Step E :

To a 3 L round bottom flask was added a stir bar, 5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine (29.68 g, 121.0 mmol) and anhydrous DCM (1190 mL ). The flask was purged with nitrogen, stirred until homogeneous and cooled to -78°C. After cooling, 1.0 MBr ₃ in DCM (364 mL, 364 mmol) was added to the flask. After 3 hours, the reaction mixture was allowed to warm to room temperature and stirred for an additional 2 hours. The reaction mixture was then carefully poured into a flask filled with ice water (300 mL) and saturated NaHCO ₃ , resulting in the formation of a tan precipitate. The resulting mixture was subjected to vacuum filtration to afford the pure title compound (86%) as a tan solid. ¹ HNMR (400MHz, CD ₃ OD), δ8.29(s, 1H), 8.04(s, 1H), 7.21–7.17(m, 1H), 7.08-7.05(d, J=8.4, 1H), 3.87– 3.78(m,1H), 2.40–2.34(m,2H), 2.23–2.12(m,2H), 2.10–2.01(m,1H), 1.91–1.85(m,1H).

Method 2 :

Step A: (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane .

Into a 500 mL three-neck round bottom flask equipped with a stir bar, temperature probe and nitrogen inlet was added 2-bromo-6-fluorophenol (25 g, 130.9 mmol, 1.00 equiv), DMF (252 mL, 0.52 M), imidazole (12.3 g , 181 mmol, 1.38 equiv) and tert-butyldimethylsilyl chloride (19.7 g, 131 mmol, 1.00 equiv). The mixture was heated at 60°C for 3 hours. The reaction was cooled to room temperature and diluted with water. The aqueous phase was extracted with ethyl acetate, the resulting organic solution was washed with water and brine, and dried over sodium sulfate. The organic phase was concentrated to dryness and purified using FCC to afford (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (33 g, 82%) as a colorless oil.

Step B: (2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane .

Into a 1 L three-neck round bottom flask equipped with a stir bar, temperature probe and nitrogen inlet was charged (2-bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (27.2 g, 89.1 mmol), THF (181.2 mL) and bis(tri-tert-butylphosphine)palladium (3.4 g, 6.68 mmol). Cyclobutylzinc bromide (267.2 mL, 134 mmol) was added and the reaction was heated at 45 °C for 22 hours. The reaction was cooled to room temperature and quenched with 1M HCl. The aqueous phase was extracted with MTBE and the combined organic extracts were washed with water, saturated aqueous thiourea, 1M HCl brine, dried over sodium sulfate and concentrated to dryness to afford (2-cyclobutyl-6-fluorophenoxy) as a pale yellow oil (tert-Butyl)dimethylsilane (24.5 g, 98%). MS (EI): mass calculated for _C16H25FOSi : _280.5 ; m/z found: 280.1 [M]. ¹ HNMR (400MHz, CDCl ₃ ), δ7.08–7.04 (m, 1H), 6.90–6.83 (m, 2H), 3.81 (tt, J=9.4, 7.8Hz, 1H), 2.32 (dtd, J=10.3 ,7.8,2.4Hz,2H),2.14–1.80(m,4H),1.03(s,9H),0.20(s,3H),0.19(s,3H).

Step C: (3-((tert-butyldimethylsilyl)oxy)-4-cyclobutyl-2-fluorophenyl)boronic acid .

In a 100 mL three necked round bottom flask equipped with a stir bar, temperature probe and nitrogen inlet was charged 2,2,6,6-tetramethylpiperidine (1.7 mL, 10 mmol) and THF (10 mL). The mixture was cooled to -78 °C and treated with 2.5M n-BuLi (4.1 mL, 10 mmol). The resulting mixture was stirred for 5 min, then warmed to 0 °C for 40 min. After 40 min, the reaction mixture was cooled to -78 °C over 10 min and treated with B(O- ^iPr ) ₃ (13.0 mL, 10.2 mmol). After stirring for 20 min, a THF solution (4 mL) of (2-cyclobutyl-6-fluorophenoxy)(tert-butyl)dimethylsilane (1.8 g, 6.3 mmol) was added within 2 min. The reaction was stirred at -78°C for 2 hours and then warmed to 0°C. Acetic acid (3.6 mL, 64 mmol) was added, the reaction was allowed to warm to room temperature and diluted with water. The resulting mixture was extracted with ethyl acetate. The organic portion was dried over sodium sulfate and concentrated to dryness to give (3-((tert-butyldimethylsilyl)-oxy)-4-cyclobutyl-2-fluorophenyl)boronic acid (1.8 g, 86%). ¹ HNMR (500MHz, CDCl ₃ ), δ7.39–7.32(m,1H), 7.18–7.13(m,1H), 5.10–4.97(m,2H), 3.82(t,J＝8.8Hz,1H), 2.41–2.06(m,5H), 2.03–1.95(m,1H), 1.03(s,9H), 0.19(s,6H).

Step D: 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol .

Add (3-((tert-butyldimethylsilyl)oxy)-4-cyclobutyl-2-fluorophenyl)boronic acid to a 50 mL three-necked flask equipped with a stir bar, nitrogen inlet, and temperature probe (1.7g, 5.3mmol), toluene (4.7mL), DMF (2.8mL) and water (4.7mL). The solvent mixture was bubbled for 30 min and then treated with 2-amino-5-bromopyrazine (923 mg, 5.3 mmol), potassium carbonate (2.19 g, 15.8 mmol) and dichloro[1,1'-bis(diphenylphosphine ) ferrocene]palladium(II) _{CH2Cl2 (} 137 mg, 0.17 mmol). The reaction mixture was heated at 80 °C for 24 hours. The reaction mixture was then cooled to room temperature, diluted with water (8 mL) and stirred for two hours. The precipitate was collected by filtration and dried overnight in a vacuum oven at 60°C to give 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (1.2g, 87%) . MS (ESI+): mass calculated for _C14H14FN3O : 260.3; _m /z found: _260.1 [M+H] ⁺ . ¹ HNMR(400MHz,DMSO),δ8.24(m,,1H),7.98(d,J=1.5Hz,1H),7.09(m,1H),7.00(d,J=8.2Hz,1H),6.57 (s,2H), 3.81-3.72(m,1H), 2.34–2.14(m,2H), 2.14–1.69(m,4H).

Example 1

5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

To a 15 mL round bottom flask was added a stir bar, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (51 mg, 0.20 mmol), 4-trifluoromethylbenzyl bromide ( 52mg, 0.22mmol), powdered KOH (42mg, 0.75mmol) and DMSO (2.0mL). The resulting mixture was stirred at room temperature for 22.5 hours, then diluted with 100 mL of EtOAc and washed with water (3 times). The organic layer was separated, dried, filtered and concentrated to dryness. The crude product was subjected to FCC to afford the title compound (54 mg, 66%) as a pale yellow solid. MS (ESI): mass calculated for _C22H19F4N3O : _417.15 ; _m /z found: 418.1 [M ₊ H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ )δ8.36-8.26(dd, J=2.5,1.4,1H), 8.02-7.99(d,J=1.5,1H),7.82-7.76(dd,J=8.8, 0.9,2H),7.74-7.68(m,2H),7.59-7.51(m,1H),7.26-7.19(d,J=8.3,1H),6.68(s,2H),5.12(s,2H), 3.79-3.69 (p, J = 8.9, 1H), 2.26-2.16 (m, 2H), 2.14-2.04 (m, 2H), 2.00-1.88 (m, 1H), 1.83-1.73 (m, 1H).

Example 2

5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 1 using 3-trifluoromethylbenzyl bromide. MS (ESI): mass calculated for _C22H19F4N3O : _417.15 ; _m /z found: 418.1 [M ₊ H] ⁺ . ¹ HNMR (600MHz, CD ₃ OD) δ8.25(s, 2H), 7.82–7.78(d, J=2.0,1H), 7.76–7.70(d, J=7.5,1H), 7.69–7.64(d, J＝7.9,1H),7.63–7.56(m,2H),7.26–7.20(m,1H),5.17(s,2H),3.83–3.72(m,1H),2.33–2.22(m,2H), 2.21–2.10(m,2H), 2.07–1.96(m,1H), 1.90–1.80(m,1H).

Example 3

5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 1 using 2-trifluoromethylbenzyl bromide. MS (ESI): mass calculated for _C22H19F4N3O : _417.15 ; _m /z found: 418.1 [M ₊ H] ⁺ . ¹ HNMR (600MHz, CD ₃ OD) δ8.29–8.22(m,2H),7.92–7.86(d,J＝7.7,1H),7.79–7.74(m,1H),7.73–7.68(m,1H) ,7.65–7.59(m,1H),7.58–7.53(m,1H),7.29–7.22(m,1H),5.23(s,2H),3.86–3.72(m,1H),2.30–2.20(m, 2H), 2.20–2.07(m,2H), 2.05–1.91(m,1H), 1.90–1.78(m,1H).

Example 4

3-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid

Using conditions similar to those described in Example 1, the title compound was prepared from 3-(bromomethyl)benzoic acid. MS (ESI): mass calculated for _C22H20FN3O3 : _393.15 ; _m /z found: 394.1 [ _M +H] ⁺ . ¹ HNMR (600MHz, CD ₃ OD) δ8.32–8.24(m,1H),8.21–8.12(dd,J＝12.3,1.6,2H),8.06–7.98(m,1H),7.73–7.66(m, 1H),7.59–7.48(m,2H),7.24–7.19(d,J＝8.2,1H),5.13(s,2H),3.85–3.75(m,1H),2.28(m,2H),2.20– 2.08 (m, 2H), 2.07–1.96 (m, 1H), 1.90–1.80 (m, 1H).

Example 5

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid

Using conditions similar to those described in Example 1, the title compound was prepared from 4-(bromomethyl)benzoic acid. MS (ESI): mass calculated for _C22H20FN3O3 : _393.42 ; _m /z found: 394.1 [ _M +H] ⁺ . ¹ HNMR (600MHz, CD ₃ OD) δ8.37–8.31(d,J=1.5,1H),8.23(s,1H),8.09–8.04(d,J=8.2,2H),7.66–7.60(m, 1H),7.60–7.56(d,J=8.0,2H),7.27–7.21(d,J=8.4,1H),5.14(s,2H),3.87–3.74(p,J=8.7,1H),2.35 –2.22 (m, 2H), 2.20 – 2.09 (m, 2H), 2.09 – 1.97 (m, 1H), 1.89 – 1.82 (m, 1H).

Example 6

5-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 1 from 1-(bromomethyl)-3-(methylsulfanyl)benzene. MS (ESI): mass calculated for _C22H22FN3O3S : _427.14 ; _m /z found: 428.1 [ _M +H] ⁺ . ¹ H NMR (600MHz, DMSO-d ₆ ) δ8.34–8.29 (dd, J=2.3,1.4,1H), 8.08–8.03 (m,1H), 8.03–7.99 (d, J=1.5,1H), 7.96 –7.91(m,1H),7.87–7.82(m,1H),7.75–7.69(m,1H),7.58–7.52(m,1H),7.25–7.20(d,J＝8.3,1H),6.71( s,2H),5.15(s,2H),3.80–3.69(m,1H),3.24(s,3H),2.28–2.16(m,2H),2.14–2.03(m,2H),2.02–1.89( m,1H), 1.86–1.74(m,1H).

Example 7

5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 1 from 1-(bromomethyl)-4-(methylsulfanyl)benzene. MS (ESI): mass calculated for _C22H22FN3O3S : _427.14 ; _m /z found: 428.1 [ _M +H] ⁺ . ¹ HNMR (600MHz,DMSO-d ₆ )δ8.36–8.27(m,1H),8.05–7.95(m,3H),7.81–7.72(m,2H),7.61–7.51(m,1H),7.27– 7.18(d,J＝8.2,1H), 5.13(s,2H), 3.81–3.71(m,1H), 3.24(s,3H), 2.27–2.18(m,2H), 2.15–2.05(m,2H ), 2.02–1.92(m,1H), 1.85–1.74(m,1H).

Example 8

5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 1 from 1-(bromomethyl)-2-(trifluoromethoxy)benzene. MS (ESI): mass calculated for _C22H19F4N3O2 : _433.14 ; m/z found: _434.1 [ _{M +} H] ⁺ . ¹ HNMR (600MHz, DMSO-d ₆ ) δ8.33–8.27 (dd, J=2.3,1.4,1H), 8.05–8.01 (m,1H), 7.73–7.68 (dd, J=7.6,1.8,1H) ,7.59–7.51(m,2H),7.51–7.41(m,2H),7.25–7.20(d,J＝8.2,1H),5.07(s,2H),3.78–3.58(m,1H),2.23– 2.12 (m, 2H), 2.12–2.01 (m, 2H), 1.96–1.86 (m, 1H), 1.82–1.73 (m, 1H).

Example 9

5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 1 from 1-(bromomethyl)-3-(trifluoromethoxy)benzene. MS (ESI): mass calculated for _C22H19F4N3O2 : _433.14 ; m/z found: _434.1 [ _{M +} H] ⁺ . ¹ HNMR (600MHz,DMSO-d ₆ )δ8.33–8.28(m,1H),8.06–8.01(m,1H),7.59–7.52(m,2H),7.52–7.45(m,2H),7.40– 7.33(m,1H),7.24–7.18(d,J=8.2,1H),5.09(s,2H),3.77–3.64(p,J=8.9,1H),2.24–2.14(m,2H),2.13 –2.01 (m, 2H), 1.98 – 1.86 (m, 1H), 1.83 – 1.72 (m, 1H).

Example 10

5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 1 from 1-(bromomethyl)-4-(trifluoromethoxy)benzene. MS (ESI): mass calculated for _C22H19F4N3O2 : _433.14 ; m/z found: _434.1 [ _{M +} H] ⁺ . ¹ HNMR (600MHz,DMSO-d ₆ )δ8.33–8.28(m,1H),8.06–8.01(m,1H),7.63–7.58(m,2H),7.57–7.52(m,1H),7.45– 7.39(m,2H),7.24–7.20(d,J＝8.2,1H),5.04(s,2H),3.76–3.65(m,1H),2.24–2.14(m,2H),2.12–2.02(m ,2H), 1.99–1.88(m,1H), 1.82–1.72(m,1H).

Example 11

5-(3-{[4-Chloro-2-(methylsulfanyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 1 from 1-(bromomethyl)-4-chloro-2-(methylsulfanyl)benzene. MS (ESI): mass calculated for _{C22H21ClFN3O3S} : _461.10 ; m/z found: _462.1 [ _M +H] ⁺ . ¹ HNMR (600MHz, DMSO-d ₆ )δ8.30–8.26(m,1H),8.03–8.00(dd,J＝2.9,1.5,1H),8.00–7.97(d,J＝1.7,1H),7.95 –7.91(m,2H),7.61–7.56(m,1H),7.28–7.23(d,J＝8.3,1H),5.45(s,2H),3.83–3.73(m,1H),3.36(s, 3H), 2.28–2.18(m,2H), 2.16–2.04(m,2H), 2.01–1.89(m,1H), 1.84–1.75(m,1H).

Example 12

1-(4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)ethanone

Using conditions similar to those described in Example 1, the title compound was prepared from 1-(4-(bromomethyl)phenyl)ethanone. MS (ESI): mass calculated for _C23H22FN3O2 : _391.17 ; _m /z found: 392.1 [M ₊ H] ⁺ . ¹ HNMR (600MHz,DMSO-d ₆ )δ8.33–8.29(m,1H),8.05–7.98(m,3H),7.66–7.61(m,2H),7.57–7.52(m,1H),7.24– 7.20(d,J=8.2,1H),5.45(s,2H),3.81-3.78(m,1H),2.61(s,3H),2.28–2.16(m,2H),2.14–2.03(m,2H ), 1.99–1.89(m,1H), 1.84–1.75(m,1H).

Example 13

5-[4-Cyclobutyl-2-fluoro-3-(pyridin-3-ylmethoxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 1, the title compound was prepared using 3-chloromethylpyridine. MS (ESI): mass calculated for C20H19FN4O: _350.15 ; m/z found: _351.1 [ _M +H] ⁺ . ¹ H NMR (600MHz, CD ₃ OD) δ9.03–8.97 (d, J=2.1,1H), 8.88–8.82 (dd, J=5.3,1.5,1H), 8.71–8.65 (m,1H), 8.28– 8.23(m,1H),8.22–8.19(d,J＝1.5,1H),8.11–8.06(m,1H),7.66–7.60(m,1H),7.29–7.23(m,1H),5.35–5.28 (s,2H),3.91–3.80(m,1H),2.39–2.29(m,2H),2.25–2.15(m,2H),2.12–2.00(m,1H),1.92–1.84(m,1H) .

Example 14

5-[4-Cyclobutyl-2-fluoro-3-(pyridin-4-ylmethoxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 1, the title compound was prepared using 4-chloromethylpyridine. MS (ESI): mass calculated for C20H19FN4O: _350.15 ; m/z found: _351.1 [ _M +H] ⁺ . ¹ HNMR (600MHz, CD ₃ OD) δ9.03–8.76(m,2H),8.33–8.16(m,4H),7.67–7.60(m,1H),7.30–7.25(m,1H),5.44(s ,2H), 3.94–3.85(m,1H), 2.42–2.32(m,2H), 2.29–2.18(m,2H), 2.12–2.02(m,1H), 1.95–1.85(m,1H).

Example 15

4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

The title compound was prepared using conditions similar to those described in Example 1 from 4-bromomethylbenzonitrile. MS (ESI): mass calculated for _C22H19FN4O : 374.15; m/z found: _375.1 [M ₊ H] ⁺ . ¹ HNMR (600MHz, CD ₃ OD) δ8.32–8.28 (d, J=1.4, 1H), 8.23 (s, 1H), 7.79–7.75 (m, 2H), 7.69–7.64 (m, 2H), 7.64 –7.58(m,1H),7.24–7.20(m,1H),5.12(s,2H),3.84–3.73(m,1H),2.32–2.23(m,2H),2.20–2.09(m,2H) ,2.08–1.96(m,1H),1.89–1.80(m,1H).

Example 16

3-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

Using conditions similar to those described in Example 1, the title compound was prepared from 3-bromomethylbenzonitrile. MS (ESI): mass calculated for _C22H19FN4O : 374.15; m/z found: _375.1 [M ₊ H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.47–8.42 (dd, J=2.3,1.5,1H), 8.10–8.06 (d, J=1.5,1H), 7.80–7.75 (m,1H), 7.73–7.67 (m,1H),7.65–7.60(m,1H),7.59–7.53(dd,J＝8.2,7.4,1H),7.52–7.47(m,1H),7.18–7.13(m,1H),5.05( s,2H),4.64(s,2H),3.81–3.67(m,1H),2.34–2.22(m,2H),2.19–2.06(m,2H),2.06–1.94(m,1H),1.92– 1.78(m,1H).

Example 17

3-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide

The title was obtained as a by-product in the formation of 3-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile (Example 16) compound. MS (ESI): mass calculated for _C22H21FN4O2 : 392.16; m/z found: _393.2 [M ₊ H] ₊ ^{. 1} HNMR (600MHz, CD ₃ OD) δ8.28–8.22 (dd, J=5.9,1.5,2H),8.03–7.98(m,1H),7.90–7.83(m,1H),7.69–7.64(m, 1H),7.61–7.55(m,1H),7.53–7.47(m,1H),7.24–7.19(dd,J＝7.4,1.0,1H),5.13(s,2H),3.86–3.75(m,1H ), 2.33–2.21(m,2H), 2.19–2.08(m,2H), 2.08–1.96(m,1H), 1.91–1.79(m,1H).

Example 18

2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile

Using conditions similar to those described in Example 1, the title compound was prepared from 2-bromomethylbenzonitrile. MS (ESI): mass calculated for _C22H19FN4O : 374.15; m/z found: _375.1 [M ₊ H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.35–8.28 (dd, J=2.5,1.4,1H), 8.03–7.97 (d, J=1.5,1H), 7.95–7.89 (m,1H), 7.83 –7.72(m,2H),7.64–7.52(m,2H),7.25–7.18(d,J＝8.3,1H),6.68(s,2H),5.20(s,2H),3.77–3.65(m, 1H), 2.25–2.12(m,2H), 2.12–2.01(m,2H), 1.96–1.85(m,1H), 1.83–1.70(m,1H).

Example 19

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzamide

The title was obtained as a by-product in the formation of 2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile (Example 18) compound. MS (ESI): mass calculated for _C22H21FN4O2 : _392.16 ; m/z found: 393.1 [M ₊ H] ₊ ^{. 1} H NMR (600MHz, CD ₃ OD) δ8.27 (s, 1H), 8.22–8.16 (d, J=1.5, 1H), 7.77–7.72 (dd, J=7.8, 1.2, 1H), 7.63–7.59 ( dd,J=7.6,1.3,1H),7.59–7.52(m,2H),7.46–7.41(m,1H),7.26–7.21(d,J=8.2,1H),5.30(s,2H),3.89 –3.77 (p, J=8.8, 1H), 2.35 – 2.23 (m, 2H), 2.20 – 2.09 (m, 2H), 2.07 – 1.96 (m, 1H), 1.89 – 1.78 (m, 1H).

Example 20

5-(4-Cyclobutyl-2-fluoro-3-{[4-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

Add a stir bar, 4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile (82mg, 0.22mmol ), NaN ₃ (576 mg, 8.85 mmol), NH ₄ Cl (557 mg, 10.4 mmol) and anhydrous DMF (2.0 mL). The resulting mixture was heated at 125°C for 21.5 hours and cooled to room temperature. The mixture was then passed through a syringe filter and the filtrate was subjected to HPLC purification to afford the title compound (47 mg, 40%) as a yellow solid. MS (ESI): mass calculated for _C22H20FN7O : _417.17 ; m/z found: 418.1 [ _M +H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.35–8.29(m,1H),8.12–8.06(m,2H),8.04–7.97(d,J＝1.5,1H),7.77–7.69(d,J =7.9,2H),7.60–7.51(m,1H),7.24–7.19(d,J=8.3,1H),5.13(s,2H),3.84–3.71(m,1H),2.28–2.18(m, 2H), 2.17–2.03(m,2H), 2.02–1.90(m,1H), 1.84–1.74(m,1H).

Example 21

5-(4-Cyclobutyl-2-fluoro-3-{[3-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

Preparation starting from 3-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzonitrile using similar conditions as described in Example 20 title compound. MS (ESI): mass calculated for _C22H20FN7O : _417.17 ; m/z found: 418.1 [ _M +H] ⁺ . ¹ HNMR (500MHz,DMSO-d ₆ )δ8.35–8.30(m,1H),8.24–8.19(m,1H),8.08–8.01(m,2H),7.73–7.63(m,2H),7.60– 7.52(m,1H),7.26–7.19(d,J＝8.2,1H),5.13(s,2H),3.83–3.72(m,1H),2.29–2.18(m,2H),2.15–2.04(m ,2H), 2.00–1.87(m,1H), 1.84–1.73(m,1H).

Example 22

5-(4-Cyclobutyl-2-fluoro-3-{[2-(1H-tetrazol-5-yl)benzyl]oxy}phenyl)pyrazin-2-amine

Using similar conditions as described in Example 20, starting from 2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-benzonitrile Preparation of the title compound. MS (ESI): mass calculated for _C22H20FN7O : _417.17 ; m/z found: 418.1 [ _M +H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ )δ8.28–8.23(m,1H),8.01–7.97(d,J＝1.5,1H),7.90–7.85(d,J＝7.7,1H),7.82(s ,1H),7.73–7.66(m,1H),7.64–7.57(d,J＝7.7,1H),7.55–7.49(m,1H),7.21–7.14(d,J＝8.3,1H),6.66( s,2H),5.37(s,2H),3.57–3.46(m,1H),2.15–2.04(m,2H),2.04–1.94(m,2H),1.93–1.82(m,1H),1.79– 1.68(m,1H).

Example 23

(4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)acetic acid

Using conditions similar to those described in Example 1, the title compound was prepared from 2-(4-(bromomethyl)phenyl)acetic acid. MS (ESI): mass calculated for _C23H22FN3O3 : _407.16 ; _m /z found: 408.1 [ _M +H] ⁺ . ¹ HNMR (600MHz, CD ₃ OD) δ8.31–8.15(m,2H),7.60(s,1H),7.54–7.47(m,1H),7.44–7.37(d,J＝7.9,2H),7.33 –7.29(d, J=7.8,2H),7.19–7.14(d,J=8.2,1H),5.01(s,2H),3.81–3.68(m,1H),3.61(s,2H),2.32– 2.20 (m, 2H), 2.18–2.05 (m, 2H), 2.04–1.94 (m, 1H), 1.88–1.77 (m, 1H).

Example 24

5-[4-Cyclobutyl-2-fluoro-3-(pyridin-2-ylmethoxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 1, the title compound was prepared using 2-chloromethylpyridine. MS (ESI): mass calculated for C20H19FN4O: _350.15 ; m/z found: _351.1 [ _M +H] ⁺ . ¹ H NMR (500MHz, CD ₃ OD) δ8.57–8.52(m,1H),8.32–8.28(dd,J＝2.3,1.5,1H),8.06–8.02(d,J＝1.5,1H),7.95– 7.90(m,1H),7.74–7.69(m,1H),7.55–7.50(m,1H),7.44–7.37(m,1H),7.24–7.18(m,1H),5.16(s,2H), 3.86–3.75(m,1H), 2.32–2.22(m,2H), 2.20–2.08(m,2H), 2.07–1.94(m,1H), 1.89–1.79(m,1H).

Example 25

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N,N-dimethylbenzenesulfonamide

Using conditions similar to those described in Example 1, the title compound was prepared from 4-(bromomethyl)-N,N-dimethylbenzenesulfonamide. MS (ESI): mass calculated for _C23H25FN4O3S : _456.16 ; _m /z found: 457.1 [M ₊ H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.50–8.44(d,J=1.4,1H),8.19–8.11(m,1H),7.83–7.74(m,2H),7.69–7.58(m,3H), 7.19–7.13(d,J=8.3,1H),5.06(s,2H),3.82–3.67(m,1H),2.74(s,6H),2.35–2.19(m,2H),2.19–2.05(m ,2H), 2.05–1.92(m,2H), 1.89–1.77(m,1H).

Example 26

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzenesulfonate

Using conditions similar to those described in Example 1, the title compound was prepared from 4-(bromomethyl)benzenesulfonamide. MS (ESI): mass calculated for _C21H21FN4O3S : _428.13 ; _m /z found: 429.1 [M ₊ H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ ) δ8.33–8.30 (dd, J=2.4,1.4,1H), 8.02–7.99 (d, J=1.5,1H), 7.90–7.84 (m,2H), 7.70 –7.64(m,2H),7.58–7.52(m,1H),7.39(s,2H),7.25–7.19(d,J＝8.3,1H),5.11(s,2H),3.79–3.63(m, 1H), 2.28–2.16(m,2H), 2.16–2.03(m,2H), 2.02–1.88(m,1H), 1.84–1.74(m,1H).

Example 27

4-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-N-methylbenzenesulfonamide

Using conditions similar to those described in Example 1, the title compound was prepared from 4-(bromomethyl)-N-methylbenzenesulfonamide. MS (ESI): mass calculated for _C22H23FN4O3S : _442.15 ; _m /z found: 443.2 [M ₊ H] ⁺ . ¹ H NMR (500MHz, DMSO-d ₆ ) δ8.34–8.29 (dd, J=2.3,1.4,1H), 8.05–7.99 (d, J=1.4,1H), 7.86–7.79 (m,2H), 7.73 –7.67(m,2H),7.60–7.53(m,1H),7.51–7.44(m,1H),7.25–7.19(d,J＝8.2,1H),5.12(s,2H),3.79–3.67( m,1H),2.46–2.37(d,J＝5.0,3H),2.27–2.15(m,2H),2.15–2.02(m,2H),2.02–1.88(m,1H),1.84–1.72(m ,1H).

Example 28

5-{4-Cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazin-2-amine

To 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50mg, 0.19mmol) and 1-(bromomethyl)-4-fluorobenzene (36μL, 0.29mmol) Add 1 potassium hydroxide pellet (approximately 125 mg) to a DMSO solution (1 mL). The reaction was stirred at room temperature for 16 hours, then filtered and purified by HPLC to give 5-{4-cyclobutyl-2-fluoro-3-[(4-fluorobenzyl)oxy]phenyl}pyrazine- 2-Amine (37 mg, 39%). MS (ESI): mass calculated for _C21H19F2N3O : _367.15 ; m/z found: 368.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.30 (d, J = 1.3, 1H), 8.22 (s, 1H), 7.58 (m, 1H), 7.50-7.43 (m, 2H), 7.20 (d, J ＝8.0,1H),7.15-7.07(m,2H),5.01(s,2H),3.83-3.68(m,1H),2.31-2.21(m,2H),2.18-1.93(m,3H),1.87 -1.78(m,1H).

Example 29

5-{4-Cyclobutyl-2-fluoro-3-[(3-fluorobenzyl)oxy]phenyl}pyrazin-2-amine

Prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-3-fluorobenzene title compound. MS (ESI): mass calculated for _C21H19F2N3O : _367.15 ; m/z found: 368.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.25 (d, J = 4.5, 2H), 7.58 (m, 1H), 7.43-7.37 (m, 1H), 7.29-7.19 (m, 3H), 7.11-7.04 (m,1H),5.05(d,J=9.9,2H),3.86-3.73(m,1H),2.34-2.21(m,2H),2.20-1.95(m,3H),1.91-1.80(m, 1H).

Example 30

5-{4-Cyclobutyl-2-fluoro-3-[(2-fluorobenzyl)oxy]phenyl}pyrazin-2-amine

Prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2-fluorobenzene title compound. MS (ESI): mass calculated for _C21H19F2N3O : _367.15 ; m/z found: 368.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.32 (d, J = 1.2, 1H), 8.22 (s, 1H), 7.59 (m, 1H), 7.53-7.48 (m, 1H), 7.42-7.35 (m ,1H),7.24-7.09(m,3H),5.11(s,2H),3.81-3.67(m,1H),2.29-2.17(m,2H),2.15-1.91(m,3H),1.88-1.75 (m,1H).

Example 31

5-{4-cyclobutyl-3-[(2,6-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 28, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-1,3-bis Fluorobenzene to prepare the title compound. MS (ESI): mass calculated for _C21H18F3N3O : _385.14 ; _m /z found: 386.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.24(s, 1H), 8.18(d, J=1.4, 1H), 7.59-7.52(m, 1H), 7.48-7.39(m, 1H), 7.20(d ,J＝7.6,1H),7.05-6.97(m,2H),5.19(s,2H),3.80-3.66(m,1H),2.26-2.15(m,2H),2.13-1.91(m,3H) ,1.86-1.79(m,1H).

Example 32

5-{4-cyclobutyl-3-[(2,3-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 28, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2,3-bis Fluorobenzene to prepare the title compound. MS (ESI): mass calculated for _C21H18F3N3O : 385.14; m/z found: _{386.1 [ M} +H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.27 (d, J = 1.2, 1H), 8.23 (s, 1H), 7.59 (m, 1H), 7.36–7.13 (m, 4H), 5.15 (d, J =1.0,2H), 3.82–3.69(m,1H), 2.29–2.19(m,2H), 2.17–1.92(m,3H), 1.90–1.78(m,1H).

Example 33

5-{4-cyclobutyl-3-[(3,4-difluorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 28, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-(bromomethyl)-1,2-bis Fluorobenzene to prepare the title compound. MS (ESI): mass calculated for _C21H18F3N3O : 385.14; m/z found: _{386.1 [ M} +H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.29 (d, J = 1.3, 1H), 8.23 (s, 1H), 7.59 (m, 1H), 7.45–7.36 (m, 1H), 7.33–7.20 (m ,3H), 5.02(s,2H), 3.85–3.72(m,1H), 2.34–2.23(m,2H), 2.21–1.97(m,3H), 1.90–1.81(m,1H).

Example 34

5-{3-[(2-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

Prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2-chlorobenzene title compound. MS (ESI): mass calculated for _C21H19ClFN3O : _383.12 ; _m /z found: 384.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.27-8.23(m,2H),7.63-7.56(m,2H),7.47-7.42(m,1H),7.38-7.32(m,2H),7.22(d ,J=7.8,1H),5.16(d,J=3.7,2H),3.85-3.72(m,1H),2.29-2.20(m,2H),2.18-1.91(m,3H),1.88-1.78( m, 1H).

Example 35

5-{3-[(3-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

Prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-3-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2-chlorobenzene title compound. MS (ESI): mass calculated for _C21H19ClFN3O : _383.12 ; _m /z found: 384.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.25(s, 2H), 7.60–7.54(m, 1H), 7.49(s, 1H), 7.39–7.33(m, 3H), 7.21(d, J＝8.3 ,1H), 5.04(s,2H), 3.84–3.70(m,1H), 2.32–2.21(m,2H), 2.20–1.94(m,3H), 1.91–1.79(m,1H).

Example 36

5-{3-[(4-Chlorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

Prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-4-chlorobenzene title compound. MS (ESI): mass calculated for _C21H19ClFN3O : _383.12 ; _m /z found: 384.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.31 (d, J = 1.3, 1H), 8.22 (s, 1H), 7.62–7.55 (m, 1H), 7.46–7.36 (m, 4H), 7.20 (d ,J=7.9,1H),5.00(d,J=9.7,2H),3.82–3.69(m,1H),2.31–2.20(m,2H),2.17–1.93(m,3H),1.90–1.78( m, 1H).

Example 37

5-{4-cyclobutyl-3-[(2,6-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 28, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-1,3-bis Chlorobenzene to prepare the title compound. MS (ESI): mass calculated for _{C21H18Cl2FN3O} : _417.08 ; _m /z found: 418.0 [M ₊ H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.29 (d, J = 1.4, 1H), 8.21 (t, J = 1.4, 1H), 7.62–7.56 (m, 1H), 7.47–7.41 (m, 2H) , 7.38–7.31 (m, 1H), 7.22 (d, J=7.7, 1H), 5.42 (s, 2H), 3.84–3.70 (m, 1H), 2.19–1.75 (m, 6H).

Example 38

5-{4-cyclobutyl-3-[(2,5-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 28, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-1,4-bis Chlorobenzene to prepare the title compound. MS (ESI): mass calculated for _{C21H18Cl2FN3O} : _417.08 ; _m /z found: 418.0 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.27–8.21(m,2H),7.66(d,J=2.5,1H),7.59(m,1H),7.47–7.41(m,1H),7.39–7.34 (m,1H),7.24(m,1H),5.13(s,2H),3.86–3.73(m,1H),2.33–2.22(m,2H),2.20–2.09(m,2H),2.07–1.96 (m,1H),1.92–1.79(m,1H).

Example 39

5-{4-cyclobutyl-3-[(2,3-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 28, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2,3-bis Chlorobenzene to prepare the title compound. MS (ESI): mass calculated for _{C21H18Cl2FN3O} : _417.08 ; _m /z found: 418.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.25(s, 2H), 7.62-7.52(m, 3H), 7.35(m, 1H), 7.23(d, J=8.3, 1H), 5.19(s, 2H ), 3.86–3.73(m,1H), 2.29–1.78(m,7H).

Example 40

5-{4-cyclobutyl-3-[(2,4-dichlorobenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 28, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2,4-bis Chlorobenzene to prepare the title compound. MS (ESI): mass calculated for _{C21H18Cl2FN3O} : _417.08 ; _m /z found: 418.0 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.27 (d, J = 1.3, 1H), 8.24 (s, 1H), 7.63-7.57 (m, 2H), 7.53 (d, J = 2.1, 1H), 7.41 -7.37(m,1H),7.23(d,J=7.9,1H),5.14(s,2H),3.84-3.72(m,1H),2.30-2.20(m,2H),2.18-1.95(m, 3H), 1.89-1.79 (m, 1H).

Example 41

5-{4-cyclobutyl-3-[(3,4-dimethylbenzyl)oxy]-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 28, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-(bromomethyl)-1,2-bis Methylbenzene to prepare the title compound. MS (ESI): mass calculated for _C23H24FN3O : _377.19 ; m/z found: 378.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.29–8.21(m,2H),7.60–7.53(m,1H),7.23–7.02(m,4H),5.02(d,J＝43.3,2H),3.82 –3.67 (m, 1H), 2.38 (s, 1H), 2.33 (s, 1H), 2.29 – 2.16 (m, 6H), 2.15 – 1.92 (m, 3H), 1.89 – 1.78 (m, 1H).

Example 42

5-(3-{[2-Chloro-3-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

In a manner similar to that described in Example 28, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-2-chloro-3 -(trifluoromethyl)benzene Preparation of the title compound. MS (ESI): mass calculated for _{C22H18ClF4N3O} : _451.11 ; _m /z found: 452.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.30-8.22 (m, 2H), 7.91 (d, J = 7.7, 1H), 7.83-7.77 (m, 1H), 7.64-7.52 (m, 2H), 7.24 (d, J=7.9,1H),5.23(d,J=6.5,2H),3.84-3.72(m,1H),2.30-2.18(m,2H),2.17-2.07(m,2H),2.07- 1.93(m,1H),1.88-1.79(m,1H).

Example 43

5-(3-{[5-Chloro-2-(trifluoromethyl)benzyl]oxy}-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine

In a manner similar to that described in Example 28, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-4-chloro-1 -(trifluoromethyl)benzene Preparation of the title compound. MS (ESI): mass calculated for _{C22H18ClF4N3O} : _451.11 ; _m /z found: 452.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.25(s, 2H), 7.92(s, 1H), 7.75(d, J=8.5, 1H), 7.66–7.60(m, 1H), 7.57(d, J =8.4,1H),7.27(d,J=7.9,1H),5.21(s,2H),3.85–3.73(m,1H),2.33–2.23(m,2H),2.20–2.11(m,2H) ,2.07–1.96(m,1H),1.91–1.82(m,1H).

Example 44

5-(4-Cyclobutyl-2-fluoro-3-{[4-fluoro-2-(trifluoromethyl)benzyl]oxy}phenyl)pyrazin-2-amine

In a manner similar to that described in Example 28, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 1-(bromomethyl)-4-fluoro-2 -(trifluoromethyl)benzene Preparation of the title compound. MS (ESI): mass calculated for _C22H18F5N3O : _435.14 ; _m /z found: _436.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.26 (d, J = 1.3, 1H), 8.23 (s, 1H), 7.92-7.86 (m, 1H), 7.61 (m, 1H), 7.55-7.51 (m ,1H),7.49-7.43(m,1H),7.24(d,J=8.0,1H),5.18(s,2H),3.83-3.70(m,1H),2.29-2.19(m,2H),2.18 -2.08(m,2H),2.06-1.93(m,1H),1.90-1.79(m,1H).

Example 45

5-{3-[(2-Chloro-5-fluorobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 28, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-(bromomethyl)-1-chloro-4 -Fluorobenzene Preparation of the title compound. MS (ESI): mass calculated for _{C21H18ClF2N3O} : _401.11 ; _m /z found: 402.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.25 (m, 2H), 7.64-7.57 (m, 1H), 7.48-7.40 (m, 2H), 7.23 (d, J = 7.9, 1H), 7.16-7.08 (m,1H),5.13(s,2H),3.87-3.75(m,1H),2.33-2.21(m,2H),2.21-1.94(m,3H),1.90-1.80(m,1H).

Example 46

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid

The title was prepared in a manner similar to that described in Example 28 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and ethyl 2-(bromomethyl)benzoate compound. MS (ESI): mass calculated for _C22H20FN3O3 : _393.15 ; _m /z found: 394.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.30 (d, J = 1.0, 1H), 8.22 (s, 1H), 8.06-8.02 (m, 1H), 7.87 (d, J = 7.7, 1H), 7.66 -7.56(m,2H),7.44(m,1H),7.22(d,J=8.3,1H),5.47(s,2H),3.87-3.72(m,1H),2.31-2.20(m,2H) ,2.17-2.07(m,2H),2.05-1.92(m,1H),1.87-1.77(m,1H).

Example 47

5-{4-cyclobutyl-2-fluoro-3-[(1-methyl-1H-pyrazol-3-yl)methoxy]phenyl}pyrazine-2-

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 3-(bromomethyl)-1-methyl- 1H-Pyrazole Preparation of the title compound. MS (ESI): mass calculated for _C19H20FN5O : _353.16 ; m/z found: _354.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.30-8.25 (m, 1H), 8.18 (m, 1H), 7.58-7.51 (m, 2H), 7.19 (d, J = 8.3, 1H), 6.34 (m ,1H),5.03(d,J=5.7,2H),3.88(d,J=6.0,3H),3.82-3.71(m,1H),2.30-2.20(m,2H),2.15-1.95(m, 3H), 1.89-1.79 (m, 1H).

Example 48

5-{4-cyclobutyl-3-[(3-cyclopropyl-1,2,4- Oxadiazol-5-yl)methoxy]-2-fluorophenyl}pyrazin-2-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 5-(bromomethyl)-3-cyclopropyl -1,2,4- oxadiazole to prepare the title compound. MS (ESI): mass calculated for _C20H20FN5O2 : _381.16 ; m/z found: 382.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.25(d, J=1.6,1H), 8.16(d, J=1.4,1H), 7.59(m,1H), 7.22(d, J=8.3,1H) ,5.26(d,J=6.7,2H),3.85-3.74(m,1H),2.36-2.25(m,2H),2.20-2.01(m,4H),1.92-1.82(m,1H),1.14- 1.05(m,2H),1.01-0.95(m,2H).

Example 49

[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy] tert-butyl acetate

Add a stir bar, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (47 mg, 0.18 mmol), tert-butyl bromoacetate (35 μL, 0.24 mmol) to a 4 mL vial , powdered KOH (19 mg, 0.34 mmol) and DMSO (1.0 mL). The resulting mixture was stirred at room temperature for 19 hours, then passed through a syringe filter and the filtrate was subjected to HPLC purification to afford the title compound (20 mg, 22%) and recovered 3-(5-aminopyrazin-2-yl) - 6-cyclobutyl-2-fluorophenol (20 mg, 26%). MS (ESI): mass calculated for C20H24FN3O3: _373.18 ; _m /z found: 374.1 _{[ M} +H] ⁺ . ¹ HNMR (600MHz, CDCl ₃ ) δ8.44–8.38(d, J=1.4,1H), 8.21–8.16(d, J=1.4,1H), 7.64–7.57(m,1H), 7.17–7.10(m ,1H),4.57–4.49(d,J＝1.3,2H),3.99–3.88(m,1H),2.41–2.30(m,2H),2.18–1.99(m,3H),1.91–1.79(m, 1H), 1.50(s, 9H).

Example 50

[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetic acid

A stir bar and formic acid ( 1 mL). The reaction mixture was stirred at room temperature for 20 hours, then concentrated to dryness to give the title compound (12 mg, 95%). MS (ESI): mass calculated for _C16H16FN3O3 : _317.12 ; _m /z found: 318.0 [ _M +H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.25(s,1H),8.14(s,1H),8.07(s,1H),7.55–7.49(m,1H),7.22–7.16(d,J＝8.2 ,1H),4.65(s,2H),4.04–3.86(p,J＝8.7,1H),2.42–2.31(m,2H),2.25–2.12(m,2H),2.12–2.00(m,1H) ,1.94–1.80(m,1H).

Example 51

Racemic 1-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridine-2(1H)- ketone

Under nitrogen, to a 5 mL reaction tube equipped with a reflux condenser was added 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazine- 2-Amine (100 mg, 0.317 mmol), _{Cs2CO3 (} 103 mg, 0.317 mmol), pyridin-2(1H)-one (151 mg, 1.59 mmol) and DMF (2 mL) gave a yellow suspension. The resulting mixture was heated at 80 °C for 3 hours. The mixture was then concentrated to dryness and the residue was purified by HPLC to give the title compound (110 mg, 85%). MS (ESI): Mass calculated for C ₂₂ H ₂₃ FN ₄ O ₃ : 410.18; m/z found: 411.1 [M+H] ⁺ ; ¹ HNMR (400MHz, DMSO-d ₆ ): δ8.29(dd ,J=2.4,1.5,1H),8.00(m,1H),7.66–7.60(m,1H),7.52(m,1H),7.46–7.39(m,1H),7.21(d,J=8.2, 1H), 6.65(s, 2H), 6.40(dd, J=9.1, 0.8, 1H), 6.21(m, 1H), 5.40(d, J=5.8, 1H), 4.35(dd, J=13.0, 3.8 ,1H),4.18–4.08(m,1H),3.93(d,J=5.1,2H),3.85(dd,J=17.8,8.9,1H),3.74(dd,J=13.0,8.4,1H), 2.30 (m, 2H), 2.13–2.04 (m, 2H), 2.03–1.94 (m, 1H), 1.88–1.78 (m, 1H).

Example 52

Racemic 3-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrimidine-4(3H)- ketone

Using conditions similar to those described in Example 51, the title compound was prepared from pyrimidin-4(3H)-one. MS (ESI): mass calculated for _C21H22FN5O3 : _411.17 ; _m /z found: _412.1 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.36(s, 1H), 8.31-8.27(m, 1H), 8.00(d, J=1.5, 1H), 7.92(d, J=6.6, 1H), 7.52(m,1H),7.22(d,J=8.2,1H),6.65(s,2H),6.43(dd,J=6.6,0.7,1H),5.53(s,1H),4.37(dd,J =13.2,3.3,1H),4.11(dd,J=8.7,3.5,1H),3.96(d,J=5.3,2H),3.90-3.82(m,1H),3.80-3.74(m,1H), 2.32 (m, 2H), 2.10 (m, 2H), 2.04-1.92 (m, 1H), 1.86-1.77 (m, 1H).

Example 53

Racemic 2-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyridazine-3(2H) -ketone

Using conditions similar to those described in Example 51, the title compound was prepared from pyridazin-3(2H)-one. MS (ESI): mass calculated for _C21H22FN5O3 : _411.17 ; _m /z found: _412.0 [M+H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ ) δ8.30-8.25 (m, 1H), 7.99 (d, J = 1.5, 1H), 7.93 (dd, J = 3.8, 1.7, 1H), 7.50 (m, 1H ),7.41(dd, J=9.4,3.8,1H),7.20(d,J=8.2,1H),6.95(dd,J=9.4,1.6,1H),6.64(s,2H),5.31(d, J=5.7,1H),4.30(m,1H),4.22(d,J=6.6,2H),3.98-3.91(m,2H),3.90-3.79(m,1H),2.28(dd,J=14.3 , 7.8, 2H), 2.08 (dd, J = 19.5, 9.4, 2H), 2.03-1.95 (m, 1H), 1.86-1.75 (m, 1H).

Example 54

Racemic 1-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)pyrazine-2(1H) -ketone

Using conditions similar to those described in Example 51, the title compound was prepared from pyrazin-2(1H)-one. MS (ESI): mass calculated for _C21H22FN5O3 : _411.17 ; _m /z found: _412.1 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.35 (d, J=1.5,1H), 8.07 (dd, J=9.7,1.3,2H), 7.66 (dd, J=4.3,1.1,1H), 7.58 (m,1H),7.39(d,J=4.3,1H),7.28(d,J=8.2,1H),6.70(s,2H),5.54(s,1H),4.41(dd,J=12.9, 3.4,1H),4.22(s,1H),4.02(d,J=5.2,2H),3.91(dd,J=17.8,8.8,1H),3.82(dd,J=12.9,9.0,1H),2.41 -2.33 (m, 2H), 2.15 (dd, J=19.1, 9.5, 2H), 2.06 (dd, J=18.7, 9.0, 1H), 1.94-1.83 (m, 1H).

Example 55

rac 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-5-ylamino)propan-2-ol

Using conditions similar to those described in Example 51, the title compound was prepared from 5-aminopyrimidine. MS (ESI): mass calculated for _C21H23FN6O2 : _{410.19 ;} m/z found: 411.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.35(s,1H),8.26-8.21(m,1H),8.17(s,2H),7.95(d,J=1.4,1H),7.47(m, 1H), 7.17(d, J=8.2, 1H), 6.60(s, 2H), 6.11(t, J=6.0, 1H), 5.26(s, 1H), 4.03-3.91(m, 3H), 3.85- 3.74(m,1H),3.24-3.11(m,2H),2.28-2.16(m,2H),2.10-1.98(m,2H),1.93-1.81(m,1H),1.80-1.69(m,1H ).

Example 56

rac 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidin-2-ylamino)propan-2-ol

Step A: 1-Amino-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol .

A solution of 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine (500 mg, 1.59 mmol) and _6NNH in MeOH (5 mL) was stirred in a sealed tube at 60 °C for about 8 hours, then cooled to room temperature and concentrated to dryness to give 1-amino-3-(3-(5-aminopyrazin-2-yl)-6 -Cyclobutyl-2-fluorophenoxy)propan-2-ol (510 mg, 96%).

Step B :

To a 25 mL round bottom flask was added a stir bar, 1-amino-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propan-2-ol ( 150 mg, 0.45 mmol), 2-chloropyrimidine (62 mg, 0.54 mmol), Cs ₂ CO ₃ (440 mg, 1.35 mmol) and DMF (6 mL). The mixture was stirred at 60°C for about 24 hours, then diluted with water (20 mL). The aqueous mixture was extracted with EtOAc (3 x 30 mL), the combined extracts _were dried over _Na2SO4 , filtered and concentrated to dryness. The residue was purified by HPLC to give the title compound (25 mg, 55%). MS (ESI): mass calculated for _C21H23FN6O2 : _{410.19 ;} m/z found: 411.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.33–8.18 (m, 3H), 7.95 (d, J = 1.4, 1H), 7.45 (m, 1H), 7.15 (d, J = 8.2, 1H), 6.98(m,1H),6.61(s,2H),6.54(m,1H),5.19(d,J=5.3,1H),4.03–3.96(m,1H),3.94–3.85(m,2H), 3.83–3.75(m,1H),3.49–3.42(m,2H),2.26–2.17(m,2H),2.09–1.97(m,2H),1.93–1.84(m,1H),1.80–1.71(m ,1H).

Example 57

rac 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrazin-2-ylamino)propan-2-ol

Using conditions similar to those described in Example 56, the title compound was prepared from 2-chloropyrazine. MS (ESI): mass calculated for _C21H23FN6O2 : _{410.19 ;} m/z found: 411.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.23(s,1H),7.95(s,1H),7.88(s,1H),7.60(s,1H),7.45(s,1H),7.22-6.96 (m,2H),6.60(s,2H),5.23(s,1H),3.98(s,2H),3.91(s,2H),3.79(s,2H),2.21(s,2H),2.03( s, 2H), 1.86 (d, J=8.5, 1H), 1.76 (s, 1H).

Example 58

Racemic 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((5-aminopyrimidin-2-yl)amino)propane -2-ol

Using conditions similar to those described in Example 56, the title compound was prepared from 2-chloro-5-aminopyrimidine. ¹ HNMR (400MHz,DMSO-d ₆ )δ9.09(s,1H),8.31-8.25(m,1H),8.00(d,J=1.5,1H),7.94(s,2H),7.49(m, 1H), 7.19(d, J=8.3, 1H), 6.64(s, 2H), 6.38(m, 1H), 5.18(d, J=5.2, 1H), 4.04-3.80(m, 4H), 3.44( m,2H), 2.32-2.21(m,2H), 2.06(m,2H), 1.92(m,1H), 1.80(m,1H).

Example 59

Racemic 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-((6-aminopyrimidin-4-yl)amino)propane -2-ol

Using conditions similar to those described in Example 56, the title compound was prepared from 4-amino-6-chloropyrimidine. MS (ESI): mass calculated for _C21H24FN7O2 : _425.20 ; m/z found: 426.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.25(s,1H),7.97(s,1H),7.84(s,1H),7.47(m,1H),7.18(d,J＝8.3,1H) ,6.61(s,2H),6.54(s,1H),6.02(s,2H),5.43(s,1H),5.34(s,1H),3.98-3.78(m,6H),2.24(s,2H ), 2.10-2.01 (m, 2H), 1.92 (dd, J=18.5, 9.0, 1H), 1.77 (d, J=9.1, 1H).

Example 60

Racemic 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-pyrazol-1-yl)propan-2- alcohol

Using conditions similar to those described in Example 51, the title compound was prepared from pyrazole. MS (ESI): mass calculated for _C20H22FN5O2 : _383.18 ; m/z found: _384.0 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.36(s, 1H), 8.01(s, 1H), 7.54-7.42(m, 3H), 7.08(d, J=8.2, 1H), 6.23(d, J= 1.9,1H),4.64(s,2H),4.43(dd,J=16.1,5.7,1H),4.32(m,2H),3.89(dd,J=9.6,4.8,1H),3.83(dd,J =9.6,5.5,1H),3.73(dd,J=17.6,8.5,1H),2.31-2.22(m,2H),2.07(dd,J=18.7,9.2,2H),2.02-1.93(m,1H ), 1.84-1.77(m,1H).

Example 61

rac 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-imidazol-1-yl)propan-2-ol

Using conditions similar to those described in Example 51, the title compound was prepared from imidazole. MS (ESI): mass calculated for _C20H22FN5O2 : _383.18 ; m/z found: _384.0 [M ₊ H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.32(s, 1H), 7.99(s, 1H), 7.48(m, 1H), 7.09(d, J=8.3, 1H), 6.11(s, 2H), 4.83(s,1H),4.32-4.08(m,3H),3.92(d,J＝12.2,2H),3.71(m,1H),2.31-2.21(m,2H),2.14-2.03(m,2H ), 2.02-1.93 (m, 1H), 1.81 (dd, J=19.5, 8.6, 1H).

Example 62

Racemic 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,4-triazole-1- base) propan-2-ol

Using conditions similar to those described in Example 51, the title compound was prepared from 1,2,4-triazole. MS (ESI): mass calculated for _C19H21FN6O2 : _{384.17 ;} m/z found: 385.0 [M ₊ H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ )δ8.36(s,1H),8.16(s,1H),8.00(s,1H),7.91(s,1H),7.50(m,1H),7.09(d,J =8.3,1H),4.63(s,2H),4.48(dd,J=16.7,6.1,1H),4.35(dd,J=14.0,4.7,2H),3.93(d,J=4.2,2H), 3.70(dd, J=17.6,8.7,1H),2.28(m,2H),2.09(dd,J=14.4,5.4,2H),2.03-1.95(m,1H),1.82(dd,J=19.2, 8.7, 1H).

Example 63

Racemic 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,3-triazole-1- base) propan-2-ol

Using conditions similar to those described in Example 51, the title compound was prepared from 1,2,3-triazole. MS (ESI): mass calculated for _C19H21FN6O2 : _{384.17 ;} m/z found: 385.0 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.38-8.32 (m, 1H), 8.01 (d, J = 1.5, 1H), 7.71 (d, J = 0.8, 1H), 7.68 (d, J = 3.8, 1H ),7.51(m,1H),7.09(d,J=8.2,1H),4.75-4.60(m,3H),4.53(dd,J=14.1,7.1,1H),4.39(dd,J=13.1, 8.0,1H),3.98(dd,J=9.8,4.9,1H),3.89(dd,J=9.9,5.9,1H),3.71(m,1H),3.38-3.13(m,1H),2.27(m ,2H), 2.14-2.05(m,2H), 2.03-1.94(m,1H), 1.81(m,1H).

Example 64

Racemic 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(2H-1,2,3-triazole-2- base) propan-2-ol

Using conditions similar to those described in Example 51, the title compound was prepared from 1,2,3-triazole. MS (ESI): mass calculated for _C19H21FN6O2 : _{384.17 ;} m/z found: 385.0 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.39-8.35 (m, 1H), 8.01 (d, J = 1.5, 1H), 7.60 (d, J = 1.7, 2H), 7.52-7.46 (m, 1H), 7.08(d, J=8.3,1H), 4.76(dd, J=13.9,4.0,1H), 4.67(d,J=7.2,1H), 4.64(d,J=7.2,2H), 4.49-4.42( m,1H),4.03-3.92(m,2H),3.75(m,1H),3.53-3.35(m,1H),2.32-2.22(m,2H),2.12-2.04(m,2H),1.98( m,1H), 1.85-1.75(m,1H).

Example 65

Racemic 5-amino-1-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)-1H- Pyrazole-4-carbonitrile

Using conditions similar to those described in Example 51, the title compound was prepared from 3-amino-4-cyanopyrazole. MS (ESI): mass calculated for _C21H22FN7O2 : _423.18 ; m/z found: _424.0 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.24(s,1H),7.95(s,1H),7.59-7.34(m,2H),7.17(d,J＝8.0,1H),6.61(s, 2H),6.44(s,2H),5.44(s,1H),4.22-4.11(m,1H),4.07-3.96(m,2H),3.92-3.86(m,2H),3.84-3.76(m, 1H), 2.29-2.20(m, 2H), 2.08-1.93(m, 3H), 1.82-1.73(m, 1H).

Example 66

Racemic 1-(5-amino-1H-1,2,3-triazol-1-yl)-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2 -fluorophenoxy)propan-2-ol

Step A: 1H-1,2,3-triazol-5-amine .

To a 25 mL round bottom flask was added a stir bar, 5-nitro-1H-1,2,3-triazole (300 mg, 2.63 mmol), Raney nickel (30 mg) and MeOH (5 mL). The flask was subjected to 1 atm of _H2 and stirred at room temperature for approximately 3 hours. The mixture was then filtered, and the filtrate was concentrated to dryness to give 1H-1,2,3-triazol-5-amine (181 mg, yield: 82%).

Step B :

Using conditions similar to those described in Example 51, the title compound was prepared from 1H-1,2,3-triazol-5-amine. MS (ESI): mass calculated for _C19H22FN7O2 : _399.18 ; m/z found: _400.0 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.25(s,1H),7.98(s,1H),7.53-7.42(m,1H),7.18(d,J＝8.5,1H),6.86(s, 1H),6.63(s,2H),5.35(d,J＝4.8,1H),4.95(s,2H),4.33-4.16(m,3H),3.89(s,2H),3.85–3.79(m, 1H), 2.32-2.21(m, 2H), 2.12–1.92(m, 3H), 1.82-1.73(m, 1H).

Example 67

Racemic 1-((1H-pyrazol-5-yl)amino)-3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propane -2-ol

5-(4-cyclobutyl-2-fluoro-3-(oxirane-2-ylmethoxy)phenyl)pyrazin-2-amine (200mg, 0.63mmol), 3-aminopyrazole (79 mg, 0.95 mmol), Yb(OTf) ₃ (80 mg, 0.13 mmol) and DMF (1 mL) was stirred at 100 °C for about 24 hours. The mixture was concentrated to dryness, and the residue was purified by HPLC to give the title compound (15%, 37 mg). MS (ESI): mass calculated for _C20H23FN6O2 : _398.19 ; m/z found: _399.0 [ _M +H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.25(s,1H),7.97(d,J=1.4,1H),7.50-7.42(m,1H),7.30(d,J=1.9,1H), 7.17(d,J=8.3,1H),6.63(s,2H),5.45(d,J=2.1,1H),5.21(s,1H),5.04(s,1H),4.04–3.73(m,5H ), 3.13–3.05(m,1H), 2.28–2.21(m,2H), 2.10–1.98(m,2H), 1.97-1.87(m,1H), 1.82-1.72(m,1H).

Example 68

5-(4-Cyclobutyl-2-fluoro-3-{[1-(methylsulfanyl)piperidin-4-yl]methoxy}phenyl)pyrazin-2-amine

Step A :

tert-butyl 4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}piperidine-1-carboxylate (50mg, 0.11mmol ) was dissolved in formic acid (1 mL) and treated with 2 equivalents of 6N HCl (solution). The mixture was stirred for 2 hours, then concentrated to give the bishydrochloride salt. The crude product was triturated with acetonitrile and purified by HPLC to give 5-(4-cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl)pyrazin-2-amine (46 mg, 98%).

Step B :

5-(4-Cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl)pyrazin-2-amine was dissolved in pyridine (0.32 mL) and washed with methanesulfonyl chloride ( 10 mg, 0.11 mmol) in DCM (0.25 mL). The reaction was stirred at room temperature for 18 hours, then concentrated to dryness. The crude product was purified by FCC to afford the title compound (6 mg, 10%). MS (ESI): mass calculated for _C21H27FN4O3S : _434.18 ; m/z found: _435.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.38 (m, 1H), 8.20 (d, J = 1.4, 1H), 7.60–7.53 (m, 1H), 7.16 (d, J = 8.2, 1H), 3.89 ( t,J＝7.8,3H),3.84–3.72(m,1H),2.81(s,3H),2.75(m,2H),2.40–2.28(m,2H),2.23–1.84(m,8H), 1.62–1.48 (m, 2H).

Example 69

5-{4-Cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (25mg, 0.096mmol), 2-chloro-4-methylpyrimidine (14mg, 0.11mmol) and K ₂ A suspension of CO ₃ (27 mg, 0.19 mmol) in DMSO (2 mL) was heated at 100° C. for 16 hours. The reaction was then cooled to room temperature, filtered, and the filtrate directly subjected to HPLC purification to give 5-{4-cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]benzene yl}pyrazin-2-amine (15 mg, 45%). MS (ESI): mass calculated for _C19H18FN5O : _351.15 ; m/z found: _352.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.37-8.33 (m, 1H), 8.26 (d, J = 1.9, 2H), 7.81-7.75 (m, 1H), 7.26 (d, J = 8.3, 1H), 7.00-6.97(m,1H),3.75-3.63(m,1H),2.52(d,J=2.0,3H),2.27-2.09(m,4H),2.04-1.92(m,1H),1.87-1.76 (m,1H).

Example 70

5-{4-cyclobutyl-2-fluoro-3-[(5-methyl-1,2,4- Oxadiazol-3-yl)methoxy]phenyl}pyrazin-2-amine

Using conditions similar to those described in Example 101 with 10% DMF in acetonitrile (as solvent) and 3-(chloromethyl)-5-methyl-1,2,4- oxadiazole to prepare the title compound. MS (ESI): mass calculated for _C18H18FN5O2 : _355.14 ; m/z found: _356.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.51–8.46 (m, 1H), 8.09 (d, J = 1.4, 1H), 7.61 (m, 1H), 7.16 (d, J = 8.2, 1H), 5.15 ( s,2H),4.72(s,2H),3.91–3.79(m,1H),2.65(s,3H),2.39–2.27(m,2H),2.20–1.96(m,3H),1.92–1.79( m, 1H).

Example 71

5-[4-Cyclobutyl-3-(cyclohexylmethoxy)-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and cyclohexylmethyl bromide. MS (ESI): mass calculated for _C21H26FN3O : _355.21 ; _m /z found: 356.1 [M+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.46(s, 1H), 8.08(d, J=1.4, 1H), 7.54–7.48(m, 1H), 7.14(d, J=8.2, 1H), 4.66( s,2H),3.88–3.77(m,3H),2.35(m,2H),2.21–1.99(m,3H),1.96–1.75(m,6H),1.74–1.68(m,1H),1.39– 1.05(m,5H).

Example 72

5-[4-Cyclobutyl-3-(cyclopropylmethoxy)-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and cyclopropylmethyl bromide. MS (ESI): mass calculated for C18H20FN3O: _313.16 ; _m /z found: 314.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.49–8.44(m,1H),8.08(d,J=1.5,1H),7.56–7.49(m,1H),7.15(d,J=8.3,1H), 4.65(s,2H),3.95–3.83(m,3H),2.42–2.32(m,2H),2.23–1.98(m,3H),1.93–1.81(m,1H),1.34–1.23(m,1H ), 0.65–0.58(m,2H), 0.36–0.29(m,2H).

Example 73

5-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylic acid ethyl ester

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and ethyl 5-(chloromethyl)-2-furancarboxylate. MS (ESI): mass calculated for _C22H22FN3O4 : _411.16 ; _m /z found: 412.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47(s, 1H), 8.09(d, J=1.4, 1H), 7.60–7.53(m, 1H), 7.17–7.11(m, 2H), 6.50(d, J=3.4,1H),5.09(s,2H),4.71(s,2H),4.38(q,J=7.1,2H),3.83–3.70(m,1H),2.35–2.25(m,2H), 2.16–1.95 (m, 3H), 1.90–1.79 (m, 1H), 1.39 (t, J=7.1, 3H).

Example 74

tert-butyl 4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}piperidine-1-carboxylate

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and tert-butyl 4-(bromomethyl)piperidine-1-carboxylate. MS (ESI): mass calculated for _C25H33FN4O3 : _456.25 ; _m /z found: 457.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.45(s, 1H), 8.09(d, J=1.4, 1H), 7.59–7.46(m, 1H), 7.15(d, J=8.3, 1H), 4.65( s,2H),4.31–4.10(m,2H),3.92–3.73(m,3H),2.92–2.63(m,2H),2.42–2.27(m,2H),2.24–1.93(m,4H), 1.94–1.80(m,3H), 1.47(s,9H), 1.44–1.21(m,2H).

Example 75

5-{4-cyclobutyl-2-fluoro-3-[(3-methyl-1,2,4- Oxadiazol-5-yl)methoxy]phenyl}pyrazin-2-amine

Using conditions similar to those described in Example 101 with 10% DMF in acetonitrile (as solvent) and 5-(chloromethyl)-3-methyl-1,2,4- oxadiazole to prepare the title compound. MS (ESI): mass calculated for _C18H18FN5O2 : _355.14 ; m/z found: _356.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47(dd, J=2.4,1.6,1H),8.09(d,J=1.5,1H),7.66–7.58(m,1H),7.17(d,J=8.1 ,1H),5.26(s,2H),4.67(s,2H),3.89–3.77(m,1H),2.46(s,3H),2.39–2.29(m,2H),2.21–1.98(m,3H ), 1.92–1.81(m,1H).

Example 76

5-(4-cyclobutyl-2-fluoro-3-{[2-methoxy-5-(pentafluoro-λ～6～-sulfanyl)benzyl]oxy}phenyl)pyrazine- 2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and 2-methoxy-5-(pentafluorothio)benzyl bromide. MS (ESI): mass calculated for C22H21F6N3O2S: _505.13 ; m/z found: _{506.1 [ M +} H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.50–8.46 (m, 1H), 8.10 (d, J = 1.5, 1H), 8.03 (d, J = 2.8, 1H), 7.72 (dd, J = 9.0, 2.8 ,1H),7.61–7.54(m,1H),7.16(d,J=8.2,1H),6.90(d,J=9.0,1H),5.11(s,2H),4.65(s,2H),3.88 (s,3H),3.85–3.73(m,1H),2.33–2.23(m,2H),2.20–2.08(m,2H),2.06–1.91(m,2H),1.91–1.78(m,1H) .

Example 77

5-(4-Cyclobutyl-2-fluoro-3-{[2-fluoro-5-(pentafluoro-λ～6～-sulfanyl)benzyl]oxy}phenyl)pyrazine-2- amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and 2-fluoro-5-(pentafluorothio)benzyl bromide. MS (ESI): mass calculated for _C21H18F7N3OS : _493.10 ; _m /z found: _494.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.49–8.46(m,1H),8.13–8.08(m,2H),7.76(m,1H),7.63–7.57(m,1H),7.21–7.14(m, 2H),5.17(s,2H),4.69(s,2H),3.82–3.72(m,1H),2.33–2.24(m,2H),2.21–2.09(m,2H),2.08–1.95(m, 1H), 1.90–1.80 (m, 1H).

Example 78

5-(4-cyclobutyl-2-fluoro-3-{[2-fluoro-4-(pentafluoro-λ～6～-sulfanyl)benzyl]oxy}phenyl)pyrazine-2- amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and 2-fluoro-4-(pentafluorothio)benzyl bromide. MS (ESI): mass calculated for _C21H18F7N3OS : _493.10 ; _m /z found: _494.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.50–8.45 (m, 1H), 8.10 (d, J=1.5, 1H), 7.79 (m, 1H), 7.66–7.58 (m, 2H), 7.53 (dd, J=9.9,2.1,1H), 7.18(d,J=8.2,1H),5.15(s,2H),4.67(s,2H),3.78(p,J=8.7,1H),2.34–2.25(m ,2H), 2.21–2.10(m,2H), 2.09–1.96(m,2H), 1.91–1.81(m,1H).

Example 79

5-(4-Cyclobutyl-2-fluoro-3-{[4-(pentafluoro-λ～6～-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and 4-(pentafluorothio)benzyl bromide. MS (ESI): mass calculated for _C21H19F6N3OS : _{475.11 ; m} /z found: 476.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.49–8.46(m,1H),8.10(d,J=1.5,1H),7.80(d,J=8.7,2H),7.62–7.55(m,3H), 7.18(d,J=8.1,1H),5.10(s,2H),4.65(s,2H),3.78(p,J=8.7,1H),2.34–2.25(m,2H),2.22–2.09(m ,2H), 2.09–1.95(m,1H), 1.91–1.81(m,1H).

instance 80

5-(4-cyclobutyl-2-fluoro-3-{[3-(pentafluoro-λ～6～-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and 3-(pentafluorothio)benzyl bromide. MS (ESI): mass calculated for _C21H19F6N3OS : _{475.11 ; m} /z found: 476.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.48(dd, J=2.2,1.6,1H),8.10(d,J=1.5,1H),7.91(s,1H),7.74(d,J=8.2,1H ),7.59(dd,J=15.1,7.3,2H),7.50(m,1H),7.17(d,J=8.1,1H),5.12(s,2H),4.67(s,2H),3.82–3.71 (m,1H), 2.33–2.24(m,2H), 2.21–2.08(m,2H), 2.08–1.95(m,1H), 1.91–1.80(m,1H).

Example 81

5-(4-cyclobutyl-2-fluoro-3-{[2-(pentafluoro-λ～6～-sulfanyl)benzyl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and 2-(pentafluorothio)benzyl bromide. MS (ESI): mass calculated for _C21H19F6N3OS : _{475.11 ; m} /z found: 476.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.49–8.46 (m, 1H), 8.10 (d, J=1.4, 1H), 7.91 (s, 1H), 7.74 (d, J=8.3, 1H), 7.64– 7.56(m,2H),7.50(m,1H),7.17(d,J=8.2,1H),5.12(s,2H),4.66(s,2H),3.76(p,J=8.7,1H), 2.33–2.24(m,2H), 2.20–2.08(m,2H), 2.07–1.94(m,1H), 1.91–1.79(m,1H).

Example 82

5-[4-Cyclobutyl-3-(cyclobutylmethoxy)-2-fluorophenyl]pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and cyclobutylmethyl bromide. MS (ESI): mass calculated for _C19H22FN3O : _327.17 ; _m /z found: 328.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47(dd, J=2.2,1.6,1H),8.08(d,J=1.5,1H),7.51(dd,J=13.7,6.1,1H),7.14(d ,J=8.0,1H),4.70(s,2H),4.00(dd,J=6.8,0.9,2H),3.88–3.78(m,1H),2.86–2.74(m,1H),2.39–2.30( m, 2H), 2.22–1.81 (m, 11H).

Example 83

5-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-pyrazin-2-amine

5-[3-(Benzyloxy)-4-chloro-2-fluorophenyl]pyrazin-2-amine (59mg, 0.18mmol), 2-dicyclohexylphosphine-2', 6'-di Methoxy-1,1'-diphenyl (6 mg, 0.01 mmol) and palladium acetate (2 mg, 0.009 mmol) were added to the vial. The vial was capped, evacuated and backfilled with _N2 . Cyclobutylzinc bromide (0.5M in THF; 0.54 mL, 0.27 mmol) was added and the mixture was heated at 65°C for 18 hours. The reaction mixture was concentrated to dryness, and the residue was subjected to FCC. Further purification by HPLC and prep-TLC afforded the title compound (6 mg, 10%). MS (ESI): mass calculated for _C21H20FN3O : _349.16 ; m/z found: 350.4 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.52–8.47(m,1H),8.10(d,J＝1.5,1H),7.59–7.53(m,1H),7.51–7.46(m,2H),7.44– 7.32(m,3H),7.16(d,J=8.1,1H),5.05(s,2H),4.65(s,2H),3.79(p,J=8.7,1H),2.34–2.23(m,2H ), 2.19–2.07(m,2H), 2.06–1.93(m,1H), 1.90–1.78(m,1H).

Example 84

4-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}benzoic acid

Add a stir bar, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50mg, 0.19mmol) and 4-(2-bromoethyl)benzoic acid (49mg , 0.21mmol) was added KOt-Bu (37mg, 0.42mmol) and DMSO (0.5mL) into a 5mL vial. The resulting mixture was stirred at room temperature for 15 hours. The mixture was passed through a syringe filter, and the filtrate was subjected to HPLC purification to afford the title compound (10 mg, 13%). MS (ESI): mass calculated for _C23H22FN3O3 : _407.16 ; _m /z found: 408.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.32(s, 1H), 8.18(s, 1H), 8.03(d, J=8.2, 2H), 7.51(m, 1H), 7.41(d, J=8.2, 2H),7.13(d,J=8.0,1H),4.26(t,J=6.6,2H),3.61–3.48(m,1H),3.18(t,J=6.7,2H),2.23–2.00(m ,4H), 1.98–1.74(m,2H).

Example 85

5-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylic acid

Dissolve ethyl 5-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}furan-2-carboxylate (48mg, 0.12mmol) in THF (2 mL) and treated with LiOH solution (1.0 N, 0.5 mL). The mixture was stirred at room temperature for 15 hours. The reaction mixture was purified using HPLC to afford the title compound. MS (ESI): mass calculated for _C20H18FN3O4 : _383.13 ; m/z found: 384.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.22–8.15(m,2H),7.50–7.43(m,1H),7.08(m,2H),6.43(d,J＝3.4,1H),5.00(s, 2H), 2.27–2.16(m,2H), 2.07–1.89(m,3H), 1.80–1.70(m,1H).

Example 86

2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-4-amine

In a manner similar to that described in Example 69, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-6-methylpyrimidin-4-amine Preparation of the title compound. MS (ESI): mass calculated for _C19H19FN6O : _{366.16 ;} m/z found: 367.2 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.29-8.24 (m, 1H), 8.08 (d, J = 1.5, 1H), 7.81 (m, 1H), 7.31 (d, J = 8.2, 1H), 6.32 (d,J=0.9,1H),3.73-3.63(m,1H),2.45(s,3H),2.32-2.18(m,4H),2.12-2.02(m,1H),1.94-1.82(m, 1H).

Example 87

5-{4-Cyclobutyl-2-fluoro-3-[(4-phenylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-phenylpyrimidine. MS (ESI): mass calculated for _C24H20FN5O : _413.17 ; m/z found: 414.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.57(d, J=5.0, 1H), 8.45(s, 1H), 8.16(s, 1H), 8.06-8.01(m, 2H), 7.89(t, J= 7.9,1H),7.54-7.45(m,4H),7.29(d,J=8.3,1H),3.82-3.70(m,1H),2.28-2.13(m,4H),2.03-1.92(m,1H ), 1.86-1.75(m,1H).

Example 88

5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfanyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

Prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-(methylthio)pyrimidine title compound. MS (ESI): mass calculated for _C19H18FN5OS : _383.12 ; m/z found: _384.2 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.24-8.18 (m, 3H), 7.78 (m, 1H), 7.30 (d, J = 8.2, 1H), 7.09 (d, J = 5.5, 1H), 3.73 -3.58(m,1H),2.32(s,3H),2.24-2.13(m,4H),2.04-1.92(m,1H),1.87-1.77(m,1H).

Example 89

5-{4-cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

Prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4,6-dimethylpyrimidine title compound. MS (ESI): mass calculated for _C20H20FN5O : _365.16 ; m/z found: 366.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.35(d, J=1.2,1H), 8.21(s,1H), 7.86-7.78(m,1H), 7.25(d,J=8.4,1H), 6.80( s, 1H), 3.77-3.65(m, 1H), 2.41(s, 6H), 2.27-2.08(m, 4H), 2.02-1.91(m, 1H), 1.85-1.75(m, 1H).

Example 90

5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-isopropylpyrimidine . MS (ESI): mass calculated for _C21H22FN5O : _379.18 ; m/z found: _380.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.56-8.51 (m, 1H), 8.31 (d, J=1.4, 1H), 8.26 (s, 1H), 7.82 (m, 1H), 7.41-7.38 (m, 1H), 7.29(d, J=8.4, 1H), 3.79-3.66(m, 1H), 3.41-3.38(m, 1H), 2.26-2.10(m, 4H), 2.07-1.94(m, 1H), 1.89-1.79(m,1H),1.52(s,6H).

Example 91

5-{4-Cyclobutyl-2-fluoro-3-[(4-thiophen-2-ylpyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

In a manner similar to that described in Example 69, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-(thiophen-2-yl) Pyrimidine to prepare the title compound. MS (ESI): mass calculated for _C22H18FN5OS : _419.12 ; m/z found: _420.2 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47(d, J=5.3,1H), 8.42-8.37(m,1H), 8.08(d,J=1.4,1H), 7.81-7.71(m,2H), 7.54-7.51(m,1H),7.34(d,J=3.2,1H),7.26(d,J=8.3,1H),7.16-7.12(m,1H),3.80-3.66(m,1H),2.29 -2.10(m,4H),2.03-1.90(m,1H),1.85-1.75(m,1H).

Example 92

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carbonitrile

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloropyrimidine-4-carbonitrile. ¹ HNMR (400MHz, CDCl ₃ ) δ8.76(d, J=4.9,5H), 8.71(d, J=1.5,5H), 8.47(d, J=6.0,4H), 7.97(s,4H), 7.93–7.82 (m, 11H), 3.74–3.61 (m, 7H), 2.25–2.10 (m, 23H), 2.03–1.91 (m, 7H), 1.81 (d, J=8.1, 6H).

Example 93

5-{4-cyclobutyl-2-fluoro-3-[(4-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-methoxypyrimidine . MS (ESI): mass calculated for _C19H18FN5O2 : _367.14 ; m/z found: _368.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.49-8.45 (m, 1H), 8.18 (d, J = 5.7, 1H), 8.08 (d, J = 1.5, 1H), 7.82-7.74 (m, 1H), 7.22(d, J=8.3,1H),6.47(d,J=5.7,1H),3.93(s,3H),3.76-3.66(m,1H),2.26-2.12(m,4H),2.03-1.91 (m,1H), 1.86-1.77(m,1H).

Example 94

5-{4-cyclobutyl-2-fluoro-3-[(5-methoxypyrimidin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-5-methoxypyrimidine . MS (ESI): mass calculated for _C19H18FN5O2 : _367.14 ; m/z found: _368.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.29-8.20 (m, 4H), 7.80-7.73 (m, 1H), 7.25 (d, J=8.2, 1H), 3.90 (s, 3H), 3.75-3.63 ( m, 1H), 2.27-2.09(m, 4H), 2.03-1.93(m, 1H), 1.85-1.76(m, 1H).

Example 95

5-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfanyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

In a manner similar to that described in Example 69, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-(methylsulfanyl) Pyrimidine to prepare the title compound. MS (ESI): mass calculated for _C19H18FN5O3S : _415.11 ; m/z found: _416.1 [ _M +H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.87(d, J=4.8,1H), 8.44(s,1H), 8.09(d,J=1.4,1H), 7.86-7.81(m,1H), 7.72( d,J=4.8,1H),7.24(s,1H),4.70(s,2H),3.73-3.63(m,1H),3.20(s,3H),2.27-2.08(m,4H),2.03- 1.93(m,1H),1.86-1.78(m,1H).

Example 96

4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidin-2-amine

3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50mg, 0.19mmol), 4-chloro-6-methylpyrimidin-2-amine (30mg, 0.20mmol ), K ₂ CO ₃ (53 mg, 0.39 mmol) and 18-crown-6 (3 mg, 0.01 mmol) in DMSO (2 mL) were heated at 140° C. for 16 hours. The reaction was then cooled to room temperature, filtered, and the filtrate directly subjected to HPLC purification to give 4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]- 6-Methylpyrimidin-2-amine (12 mg, 16%). MS (ESI): mass calculated for _C19H19FN6O : _{366.16 ;} m/z found: 367.3 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.27-8.22 (m, 1H), 8.11 (d, J = 1.5, 1H), 7.78 (m, 1H), 7.29 (d, J = 8.3, 1H), 6.67 (d,J=0.8,1H),3.68-3.55(m,1H),2.51(d,J=0.7,3H),2.31-2.13(m,4H),2.11-1.98(m,1H),1.91- 1.81(m,1H).

Example 97

5-{4-cyclobutyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidine . MS (ESI): mass calculated for _C19H18FN5O2 : _367.14 ; m/z found: _368.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47–8.46(m,1H),8.43–8.42(m,1H),8.09–8.08(m,1H),7.82–7.78(m,1H),7.23–7.21( m,1H),6.26–6.25(m,1H),4.67(s,2H),4.00(s,3H),3.64–3.57(m,1H),2.25–2.11(m,4H),2.01–1.92( m,1H), 1.84–1.78(m,1H).

Example 98

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol

Using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidine, the title was obtained as a by-product of the reaction described in Example 96 compound. MS (ESI): mass calculated for _C18H16FN5O2 : _353.13 ; m/z found: _354.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.32–8.30(m,1H),8.15–8.13(m,1H),8.00–7.98(m,1H),7.78–7.73(m,1H),7.54–7.52( m,1H),7.28–7.24(m,1H),5.73(s,1H),3.67–3.61(m,1H),2.34–2.25(m,2H),2.24–2.14(m,2H),2.09– 1.99(m,1H),1.91–1.82(s,1H).

Example 99

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-methoxypyrimidin-2-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidine-2- Amines to prepare the title compound. MS (ESI): mass calculated for _C19H19FN6O2 : _382.15 ; m/z found: _383.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.26–8.21(m,2H),7.81–7.74(m,1H),7.31–7.26(m,1H),5.67(s,1H),3.93(s,3H ), 3.67–3.57(m,1H), 2.30–2.13(m,4H), 2.08–1.97(m,1H), 1.89–1.80(m,1H).

instance 100

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methoxypyrimidin-4-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 6-chloro-2-methoxypyrimidine-4- Amines to prepare the title compound. MS (ESI): mass calculated for _C19H19FN6O2 : _382.15 ; m/z found: _383.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.27-8.18 (m, 2H), 7.82 (CDCl ₃ , 1H), 7.33 (d, J=8.3, 1H), 5.69 (d, J=8.6, 1H), 3.86 (d, J = 8.8, 3H), 3.71 - 3.59 (m, 1H), 2.32 - 2.15 (m, 4H), 2.10 - 2.00 (m, 1H), 1.87 (t, J = 9.0, 1H).

Example 101

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzonitrile

Add a stir bar, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (50mg, 0.19mmol) and 4-fluorobenzonitrile (26mg, 0.21mmol) To a 5 mL vial was added Cs ₂ CO ₃ (96 mg, 0.29 mmol) and 0.55 mL DMSO. The resulting mixture was stirred at 80°C for about 15 hours. The mixture was cooled to room temperature, then passed through a syringe filter. The filtrate was subjected to FCC to afford the title compound (36 mg, 52%). MS (ESI): mass calculated for _C21H17FN4O : _360.14 ; m/z found: 361.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.46–8.42(m,1H),8.11–8.08(d,J＝1.5,1H),7.85–7.78(m,1H),7.63–7.56(m,2H), 7.29–7.23(m,1H),6.97–6.90(m,2H),4.77–4.66(s,2H),3.63–3.51(m,1H),2.26–2.07(m,4H),2.03–1.89(m ,1H), 1.87–1.76 (m,1H).

Example 102

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

Using conditions similar to those described in Example 101, the title compound was prepared from 2-fluoro-6-(trifluoromethyl)pyridine. MS (ESI): mass calculated for _C20H16F4N4O : 404.13; m/z found: 405.1 [ _{M +} H] ₊ ^{. 1} HNMR (400MHz, CDCl ₃ ) δ8.45(dd, J=2.4,1.6,1H),8.09(d,J=1.5,1H),7.84(dd,J=11.7,4.0,1H),7.81–7.75 (m,1H),7.37(d,J=7.3,1H),7.23(d,J=8.1,1H),7.12(d,J=8.4,1H),4.65(s,2H),3.64(p, J=8.8,1H), 2.23–2.07(m,4H), 2.00–1.87(m,1H), 1.85–1.74(m,1H).

Example 103

Methyl 4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoate

Using conditions similar to those described in Example 101, the title compound was prepared from methyl 4-fluorobenzoate. MS (ESI): mass calculated for _C22H20FN3O3 : _393.15 ; _m /z found: 394.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.46 (d, J = 1.2, 1H), 8.19 (d, J = 1.0, 1H), 8.03–7.96 (m, 2H), 7.87 (m, 1H), 7.30 ( d,J=8.4,1H),6.88(d,J=8.8,2H),3.90(s,3H),3.68–3.57(m,1H),2.26–2.06(m,4H),2.02–1.88(m ,1H),1.86–1.75(m,1H)

Example 104

5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 from 2-chloro-5-(trifluoromethyl)-pyrimidine. MS (ESI): mass calculated for _C19H15F4N5O : _405.12 ; m/z found: _406.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.81(d, J=0.6,2H),8.48–8.43(m,1H),8.09(d,J=1.5,1H),7.88–7.79(m,1H), 7.25(d,J=8.3,1H),4.76(s,2H),3.67(p,J=8.9,1H),2.27–2.08(m,4H),2.05–1.90(m,1H),1.88–1.76 (m,1H).

Example 105

5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)pyrazin-2-amine

Using conditions similar to those described in Example 101, the title compound was prepared from 2-chloro-5-(trifluoromethyl)pyrazine. MS (ESI): mass calculated for _C19H15F4N5O : _405.12 ; m/z found: _406.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.60(d, J=0.9,1H), 8.47–8.43(m,1H), 8.41(d, J=0.4,1H), 8.09(d, J=1.5,1H ),7.84(m,1H),7.25(d,J=8.7,1H),4.71(s,2H),3.60(p,J=8.8,1H),2.26–2.08(m,4H),2.05–1.91 (m,1H),1.89–1.75(m,1H).

Example 106

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridazin-3-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 from 3-chloro-6-trifluoromethyl-pyridazine. MS (ESI): mass calculated for _C19H15F4N5O : _405.12 ; m/z found: _406.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.46–8.43(m,1H),8.08(d,J=1.4,1H),7.88–7.79(m,2H),7.43(d,J=9.1,1H), 7.23(d,J＝8.3,1H),4.67(s,2H),3.68–3.56(m,1H),2.24–2.14(m,4H),2.03–1.89(m,1H),1.87–1.77(m ,1H).

Example 107

Methyl 6-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carboxylate

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and methyl 6-fluoronicotinate. MS (ESI): mass calculated for _C21H19FN4O3 : _394.14 ; _m /z found: _395.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.77(dd, J=2.3,0.5,1H),8.46(s,1H),8.31(dd,J=8.6,2.3,1H),8.08(d,J=1.3 ,1H),7.83–7.76(m,1H),7.23(d,J＝8.3,1H),7.04(dd,J＝8.6,0.6,1H),4.68(s,2H),3.91(s,3H) ,3.67–3.55(m,1H),2.23–2.07(m,4H),2.00–1.87(m,1H),1.85–1.75(m,1H).

Example 108

5-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and 2-cyano-5-fluoropyridine. MS (ESI): mass calculated for _C20H16FN5O : _361.13 ; m/z found: 362.0 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47(d, J=2.8,1H),8.45–8.41(m,1H),8.10(d,J=1.5,1H),7.88–7.81(m,1H), 7.63(d,J=8.6,1H),7.28(d,J=7.7,1H),7.19–7.12(m,1H),4.79(s,2H),3.58(p,J=8.8,1H),2.26 –2.07 (m, 4H), 2.05 – 1.91 (m, 1H), 1.89 – 1.78 (m, 1H).

Example 109

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

Using conditions similar to those described in Example 101, the title compound was prepared from 4-chloro-pyridine-2-carbonitrile. MS (ESI): mass calculated for C20H16FN5O: _361.13 ; m/z found: _362.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.54(d, J=5.7,1H),8.47–8.43(m,1H),8.10(d,J=1.2,1H),7.88(m,1H),7.32– 7.25(m,1H),7.22(d,J=2.3,1H),6.99(dd,J=5.7,2.4,1H),4.74(s,2H),3.54(p,J=8.9,1H),2.25 –2.08 (m, 4H), 2.05 – 1.92 (m, 1H), 1.89 – 1.79 (m, 1H).

Example 110

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile

Using conditions similar to those described in Example 101, the title compound was prepared from 3-cyano-2-fluoropyridine. MS (ESI): mass calculated for C20H16FN5O: _361.13 ; m/z found: _362.1 [ _M +H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.48–8.44 (m, 1H), 8.29 (dd, J = 5.0, 1.9, 1H), 8.09 (d, J = 1.5, 1H), 8.03 (dd, J = 7.6 ,1.9,1H),7.86–7.78(m,1H),7.23(d,J=8.3,1H),7.11(dd,J=7.6,5.0,1H),4.66(s,2H),3.65(p, J=8.9,1H), 2.29–2.11(m,4H), 2.06–1.92(m,1H), 1.87–1.76(m,1H).

Example 111

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

Using conditions similar to those described in Example 101, the title compound was prepared from 2-cyano-6-fluoropyridine. MS (ESI): mass calculated for C20H16FN5O: _361.13 ; m/z found: _362.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.46(dd, J=2.2,1.6,1H),8.10(d,J=1.5,1H),7.86–7.76(m,2H),7.42(dd,J=7.3 ,0.7,1H),7.25–7.19(m,2H),4.69(s,2H),3.59(p,J＝8.9,1H),2.22–2.09(m,4H),1.99–1.87(m,1H) ,1.86–1.76(m,1H).

Example 112

3-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-2-carbonitrile

Using conditions similar to those described in Example 101, the title compound was prepared from 2-cyano-3-fluoropyridine. MS (ESI): mass calculated for C20H16FN5O: _361.13 ; m/z found: _362.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.44(dd, J=2.2,1.6,1H),8.39(dd,J=4.5,1.2,1H),8.10(d,J=1.5,1H),7.89–7.80 (m,1H),7.39(dd,J=8.7,4.5,1H),7.28(d,J=7.2,1H),7.02(m,1H),4.78(s,2H),3.69–3.58(m, 1H), 2.31–2.09(m,4H), 2.07–1.94(m,1H), 1.89–1.78(m,1H).

Example 113

5-(4-Cyclobutyl-2-fluoro-3-{[5-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101 using 10% DMF in acetonitrile as solvent and 2-fluoro-5-(trifluoromethyl)pyridine. MS (ESI): mass calculated for _C20H16F4N4O : 404.13; m/z found: 405.1 [ _{M +} H] ₊ ^{. 1} HNMR (400MHz, CDCl ₃ ) δ8.46(s, 1H), 8.40(s, 1H), 8.08(d, J=1.4, 1H), 7.93(dd, J=8.7, 2.3, 1H), 7.80( m,1H),7.23(d,J=8.3,1H),7.12(d,J=8.7,1H),4.70(s,2H),3.61(p,J=8.9,1H),2.25–2.08(m ,4H), 2.00–1.89(m,1H), 1.86–1.75(m,1H).

Example 114

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carbonitrile

The title compound was prepared using conditions similar to those described in Example 101 with 10% DMF in acetonitrile as solvent and with 5-cyano-2-fluoropyridine. MS (ESI): mass calculated for C20H16FN5O: _361.13 ; m/z found: _362.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47–8.41 (m, 2H), 8.09 (d, J=1.5, 1H), 7.96 (dd, J=8.6, 2.3, 1H), 7.84–7.78 (m, 1H ),7.23(d,J=8.3,1H),7.13(dd,J=8.6,0.6,1H),4.70(s,2H),3.58(p,J=8.9,1H),2.23–2.08(m, 4H), 2.02–1.89(m,1H), 1.86–1.75(m,1H).

Example 115

5-{4-cyclobutyl-2-fluoro-3-[4-(pentafluoro-λ～6～-sulfanyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared from 4-fluorophenylsulfur pentafluoride by heating under microwave irradiation at 130°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C20H17F6N3OS : 461.10; m/z found: _{462.0 [ M} +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.42 (d, J=1.2, 1H), 8.21 (s, 1H), 7.87 (m, 1H), 7.73–7.65 (m, 2H), 7.34–7.27 (m, 1H),6.89(d,J=8.9,2H),3.90(s,2H),3.68–3.56(m,1H),2.30–2.19(m,2H),2.19–2.09(m,2H),2.06– 1.92(m,1H),1.89–1.75(m,1H).

Example 116

5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfanyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared from 4-fluorophenylmethylsulfone using conditions similar to those described in Example 101 by heating under microwave irradiation at 130°C for 1 hour. MS (ESI): mass calculated for _C21H20FN3O3S : _413.12 ; m/z found: _414.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47 (d, J = 1.2, 1H), 8.18 (s, 1H), 7.94–7.84 (m, 3H), 7.31 (d, J = 8.4, 1H), 7.00 ( d,J＝8.8,2H), 3.61(p,J＝8.9,1H), 3.08(s,3H), 2.29–2.07(m,4H), 2.05–1.91(m,1H), 1.88–1.77(m ,1H).

Example 117

5-{4-Cyclobutyl-2-fluoro-3-[2-(methylsulfanyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared from 2-fluorophenylmethylsulfone using conditions similar to those described in Example 101 by heating under microwave irradiation at 120°C for 1 hour. MS (ESI): mass calculated for _C21H20FN3O3S : _413.12 ; m/z found: _414.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.44–8.41(m,1H),8.11–8.06(m,2H),7.87–7.80(m,1H),7.46(m,1H),7.33(d,J= 8.3,1H),7.18(m,1H),6.64(d,J=8.4,1H),4.74(s,2H),3.73(p,J=8.7,1H),3.38(s,3H),2.45– 2.33 (m, 1H), 2.29–2.16 (m, 1H), 2.12–1.90 (m, 3H), 1.86–1.75 (m, 1H).

Example 118

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

The title compound was prepared from 2-bromopyrimidine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C18H16FN5O : _337.13 ; m/z found: _338.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.57(d, J=4.8,2H),8.49–8.45(m,1H),8.09(d,J=1.5,1H),7.83–7.77(m,1H), 7.24(d,J=8.2,1H),7.83–7.78(m,1H),4.66(s,2H),3.70(p,J=8.8,1H),2.27–2.08(m,4H),2.03–1.89 (m,1H),1.85–1.75(m,1H).

Example 119

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine

Method 1 :

The title compound was prepared from 4-amino-2-chloropyrimidine by heating under microwave irradiation at 120°C for 2 hours using conditions similar to those described in Example 101.

Method 2 :

3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (17.0g, 65.6mmol), K ₂ CO ₃ (13.6g, 98.4mmol), 2-chloropyrimidine- A mixture of 4-amine (8.9 g, 69 mmol), 18-crown-6 (0.87 g, 3.3 mmol) and DMA (131 mL) was stirred at 120 °C for 15 hours. Water (306 mL) was added and the reaction mixture was cooled to room temperature. The solid precipitate was collected by vacuum filtration and dried in a vacuum oven at 70 °C overnight to give the crude product (23.1 g, 100%). The solid was recrystallized from EtOH and treated sequentially with charcoal and silica-supported thiol to remove residual Pd and afford the title compound (13.0 g, 56%). MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.2 [M+H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ ) δ8.25(s, 1H), 8.01(d, J=1.5, 1H), 7.83(d, J=5.8, 1H), 7.66(, m1H), 7.23(d ,J=8.3,1H),7.06(s,2H),6.67(s,2H),6.17(d,J=5.8,1H),3.60–3.47(m,1H),2.19–2.01(m,4H) ,1.98–1.85(m,1H),1.80–1.68(m,1H).

Example 120

5-{3-[3,4-Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared from 3,4-bis-(trifluoromethyl)fluorobenzene by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C22H16F7N3O : _471.12 ; _m /z found: _472.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.45(dd, J=2.2,1.6,1H),8.09(d,J=1.5,1H),7.89–7.82(m,1H),7.74(d,J=8.8 ,1H),7.42(d,J=2.5,1H),7.29(d,J=8.3,1H),7.00(dd,J=8.8,2.1,1H),4.76(s,2H),3.59(p, J=8.8,1H), 2.27–2.07(m,4H), 2.05–1.91(m,1H), 1.88–1.76(m,1H).

Example 121

5-(4-Cyclobutyl-2-fluoro-3-{[3-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared from 2-fluoro-3-(trifluoromethyl)pyridine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C20H16F4N4O : 404.13; m/z found: 405.1 [ _{M +} H] ₊ ^{. 1} HNMR (500MHz, CDCl ₃ ) δ8.46(s, 1H), 8.24(d, J=3.7, 1H), 8.08(s, 1H), 8.01(d, J=7.7, 1H), 7.80(m, 1H), 7.23(d, J=8.4, 1H), 7.13–7.06(m, 1H), 4.62(s, 2H), 3.71–3.60(m, 1H), 2.28–2.05(m, 4H), 2.01– 1.89(m,1H),1.84–1.74(m,1H).

Example 122

5-{3-[(3-Chloropyridin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared from 3-chloro-2-fluoropyridine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C19H16ClFN4O : _370.10 ; m/z found: 371.1 [M ₊ H] ⁺ . ¹ HNMR (600MHz, DMSO-d ₆ ) δ8.23(s, 1H), 8.00(d, J=1.5, 1H), 7.82(d, J=5.8, 1H), 7.63(m, 1H), 7.22( d,J=8.3,1H),7.04(s,2H),6.65(s,2H),6.17(d,J=5.8,1H),2.14–2.01(m,4H),1.94–1.84(m,1H ), 1.76–1.69(m,1H).

Example 123

5-{3-[2-Chloro-4-(methylsulfanyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared from 2-chloro-1-fluoro-4-methylsulfanylbenzene by heating under microwave irradiation at 80°C for 2 hours using conditions similar to those described in Example 101. MS (ESI): mass calculated for _{C21H19ClFN3O3S} : _447.08 ; _m /z found: 448.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.30–8.26(m,1H),8.13(d,J=2.3,1H),8.01(d,J=1.5,1H),7.85–7.74(m,2H ),7.38(d,J=8.3,1H),6.87(dd,J=8.7,1.1,1H),6.72(s,2H),3.24(s,3H),2.17–2.07(m,4H),1.96 –1.84(m,1H),1.81–1.69(m,1H).

Example 124

5-(4-Cyclobutyl-2-fluoro-3-{[2-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared from 4-chloro-2-(trifluoromethyl)pyrimidine by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C19H15F4N5O : _405.12 ; m/z found: _406.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.75(d, J=5.7,1H), 8.46–8.42(m,1H), 8.09(d,J=1.4,1H), 7.84(m,1H), 7.24( d,J=8.3,1H),7.12(d,J=5.7,1H),4.74(s,2H),3.64–3.52(m,1H),2.24–2.08(m,4H),2.05–1.90(m ,1H), 1.87–1.77(m,1H).

Example 125

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared from 4-chloro-6-trifluoromethylpyrimidine by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C19H15F4N5O : _405.12 ; m/z found: _406.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.86(s, 1H), 8.48–8.42(m, 1H), 8.09(d, J=1.5, 1H), 7.91–7.82(m, 1H), 7.38(d, J=1.0,1H),7.28–7.22(m,1H),4.73(s,2H),3.58(p,J=8.8,1H),2.27–2.09(m,4H),2.05–1.91(m,1H ), 1.88–1.76(m,1H).

Example 126

5-{4-Cyclobutyl-2-fluoro-3-[3-methyl-4-(methylsulfanyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared from 4-fluoro-2-methyl-1-(methylsulfanyl)benzene by heating under microwave irradiation at 120°C for 2 hours using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C22H22FN3O3S : _427.14 ; _m /z found: 428.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.46–8.43(m,1H),8.10(d,J=1.5,1H),7.95(d,J=8.8,1H),7.85–7.78(m,1H), 7.27(d, J=9.3,1H),6.84(d,J=2.5,1H),6.78(dd,J=8.8,2.6,1H),4.85(s,2H),3.58(p,J=8.9, 1H), 3.07(s,3H), 2.26–2.07(m,4H), 2.00–1.90(m,1H), 1.87–1.75(m,1H).

Example 127

5-(4-Cyclobutyl-2-fluoro-3-(4-(methylsulfanyl)-2-(trifluoromethyl)phenoxy)phenyl)pyrazin-2-amine

The title compound was prepared from 2-chloro-5-methylsulfanylbenzotrifluoride by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _{C22H19F4N3O3S} : _481.11 ; _m /z found: 482.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.46–8.41 (m, 1H), 8.28 (d, J = 2.2, 1H), 8.09 (d, J = 1.5, 1H), 7.96 (dd, J = 8.8, 2.3 ,1H),7.89–7.83(m,1H),7.30(d,J=8.3,1H),6.82(d,J=8.8,1H),4.79(s,2H),3.62(p,J=8.8, 1H), 3.09(s,3H), 2.43–1.91(m,4H), 1.88–1.69(m,2H).

Example 128

5-(4-Cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared from 5-fluoro-2-(trifluoromethyl)pyridine by heating under microwave irradiation at 80°C for 2 hours using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C20H16F4N4O : 404.13; m/z found: 405.1 [ _{M +} H] ₊ ^{. 1} HNMR (400MHz, CDCl ₃ ) δ8.47(d, J=2.8,1H), 8.44(dd, J=2.2,1.7,1H), 8.09(d, J=1.5,1H), 7.86–7.80(m ,1H),7.60(d,J=8.7,1H),7.28(d,J=7.8,1H),7.19(dd,J=8.7,2.8,1H),4.78(s,2H),3.61(p, J=8.8,1H), 2.28–2.08(m,4H), 2.04–1.91(m,1H), 1.88–1.78(m,1H).

Example 129

5-{4-cyclobutyl-2-fluoro-3-[(3-methoxypyridin-2-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared from 2-fluoro-3-methoxypyridine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C20H19FN4O2 : _366.15 ; m/z found: 367.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.27(s, 1H), 8.20(s, 1H), 7.84–7.77(m, 1H), 7.63(dd, J=5.0,1.4,1H), 7.27–7.21( m,2H),6.99(dd,J＝7.9,4.9,1H),4.01(s,3H),3.74–3.61(m,1H),2.25–2.11(m,4H),2.01–1.88(m,1H ), 1.87–1.74(m,1H).

Example 130

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine

The title compound was prepared from 2-amino-4-chloropyrimidine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.48–8.45(m,1H),8.15(d,J=5.7,1H),8.06(d,J=1.5,1H),7.81–7.75(m,1H), 7.20(d,J=8.3,1H),6.25(d,J=5.7,1H),5.01(s,2H),4.70(s,2H),3.59(p,J=8.9,1H),2.30–2.07 (m,4H), 2.04–1.90(m,1H), 1.87–1.75(m,1H).

Example 131

5-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)pyrimidin-2-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared from 2-chloro-4-(trifluoromethyl)pyrimidine by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C19H15F4N5O : _405.12 ; m/z found: _406.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.77(d, J=4.8,1H), 8.45(dd, J=2.1,1.7,1H), 8.09(d, J=1.5,1H), 7.87–7.78(m ,1H),7.39(d,J=4.9,1H),7.24(d,J=8.3,1H),4.68(s,2H),3.70(p,J=8.9,1H),2.26–2.08(m, 4H), 2.03–1.90(m,1H), 1.86–1.76(m,1H).

Example 132

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5-(methylsulfanyl)benzonitrile

The title compound was prepared from 2-fluoro-5-(methylsulfanyl)benzonitrile by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C22H19FN4O3S : _438.12 ; _m /z found: 439.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, THF-d ₈ ) δ8.44(d, J=2.3,1H), 8.39(dd, J=2.6,1.5,1H), 8.08–7.96(m,3H), 7.37(d,J =8.3,1H),6.98(dd,J=8.9,1.5,1H),6.08(s,2H),3.76–3.65(m,1H),3.12(s,3H),2.35–2.18(m,4H) ,2.12–1.99(m,1H),1.94–1.82(m,1H).

Example 133

5-{4-Cyclobutyl-2-fluoro-3-[4-(methylsulfanyl)-3-(trifluoromethyl)phenoxy]phenyl}pyrazin-2-amine

The title compound was prepared from 5-bromo-2-(methylsulfanyl)benzotrifluoride by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _{C22H19F4N3O3S} : _481.11 ; _m /z found: 482.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47–8.42(m,1H),8.21(d,J=8.9,1H),8.10(d,J=1.5,1H),7.90–7.82(m,1H), 7.49 (d, J=2.6, 1H), 7.29 (d, J=8.3, 1H), 7.04 (dd, J=8.9, 2.5, 1H), 4.75 (s, 2H), 3.57 (p, J=8.8, 1H), 3.18(s,3H), 2.27–2.09(m,4H), 2.05–1.92(m,1H), 1.89–1.78(m,1H).

Example 134

5-{4-Cyclobutyl-2-fluoro-3-[(2-methylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared from 4-chloro-2-methylpyrimidine by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C19H18FN5O : _351.15 ; m/z found: _352.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.51–8.43 (m, 2H), 8.09 (d, J = 1.3, 1H), 7.80 (m, 1H), 7.23 (d, J = 8.3, 1H), 6.70 ( d,J＝5.8,1H), 4.71(s,2H), 3.59(p,J＝8.9,1H), 2.55(s,3H), 2.25–2.07(m,4H), 2.03–1.89(m,1H ), 1.87–1.72(m,1H).

Example 135

5-(4-Cyclobutyl-2-fluoro-3-{[2-(1-methylethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared from 4-chloro-2-isopropyl-pyrimidine by heating under microwave irradiation at 80°C for 2 hours using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C21H23FN6O : 394.2; m/z found: _{395.1 [} M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.52 (d, J=5.7, 1H), 8.47–8.44 (m, 1H), 8.10 (d, J=1.4, 1H), 7.80 (m, 1H), 7.22 ( d,J=8.3,1H),6.73(d,J=5.7,1H),4.69(s,2H),3.61(p,J=8.8,1H),3.02(hept,J=6.9,1H),2.24 –2.06 (m, 4H), 2.03 – 1.88 (m, 1H), 1.86 – 1.75 (m, 1H), 1.19 (d, J=6.9, 6H).

Example 136

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared from 4-amino-6-chloropyrimidine by heating under microwave irradiation at 120°C for 3 hours using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.3 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.49–8.44(m,1H),8.25(d,J=0.6,1H),8.08(d,J=1.5,1H),7.81–7.74(m,1H), 7.21(d,J=8.2,1H),5.94(d,J=0.9,1H),4.97(s,2H),4.73(s,2H),3.61(p,J=8.8,1H),2.29–2.09 (m,4H), 2.04–1.90(m,1H), 1.87–1.77(m,1H).

Example 137

5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared from 2,4-dichloropyrimidine by heating under microwave irradiation at 80°C for 2 hours using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C18H15ClFN5O : _371.09 ; m/z found: _372.1 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.67(d, J=5.7,1H),8.25(s,1H),8.02(d,J=1.4,1H),7.77(m,1H),7.37– 7.29 (m, 2H), 6.70 (s, 2H), 3.55–3.43 (m, 1H), 2.17–2.00 (m, 4H), 1.98–1.83 (m, 1H), 1.81–1.68 (m, 1H).

Example 138

5-{3-[(6-azetidin-1-ylpyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine trifluoroacetate

The title compound was prepared from 4-azetidin-1-yl-6-chloro-pyrimidine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C21H21FN6O : _{392.18 ;} m/z found: 393.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.46(d, J=1.1, 1H), 8.35(s, 1H), 8.06(d, J=0.9, 1H), 7.87(m, 1H), 7.24(d, J＝8.4,1H), 5.77(s,1H), 4.33(t, J＝7.1,4H), 3.57(p, J＝8.8,1H), 2.63–2.52(m,2H), 2.29–2.07(m ,4H), 2.08–1.93(m,1H), 1.90–1.77(m,1H).

Example 139

6-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-N,N-dimethyl-2-(trifluoromethyl)pyrimidine-4 -amine

The title compound was prepared from (6-chloro-2-trifluoromethylpyrimidin-4-yl)dimethyl-amine by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C21H20F4N6O : 448.16 _; m/z found: 449.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.45(s, 1H), 8.07(d, J=1.4, 1H), 7.82–7.74(m, 1H), 7.22(d, J=8.3, 1H), 5.84( s,1H), 4.79(s,2H), 3.62(p,J=8.9,1H), 3.11(s,6H), 2.27–2.07(m,4H), 2.03–1.75(m,2H).

Example 140

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-methylpyrimidin-4-amine trifluoroacetate

The title compound was prepared from 4-amino-6-chloro-2-methylpyrimidine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C19H19FN6O : _{366.16 ;} m/z found: 367.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.25 (d, J = 1.7, 1H), 8.11 (d, J = 1.5, 1H), 7.82 (m, 1H), 7.34 (d, J = 8.2, 1H) ,6.03(s,1H),3.69–3.57(m,1H),2.48(s,3H),2.33–2.13(m,4H),2.12–1.97(m,1H),1.92–1.81(m,1H) .

Example 141

5-{4-cyclobutyl-3-[(6-cyclopropylpyrimidin-4-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared from 4-chloro-6-cyclopropyl-pyrimidine by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C21H20FN5O : _377.16 ; m/z found: 378.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.56(d, J=0.7,1H), 8.47(d, J=1.8,1H), 8.08(d, J=1.5,1H), 7.84–7.77(m,1H ),7.22(d,J=8.3,1H),6.83(d,J=1.0,1H),4.65(s,2H),3.59(p,J=9.0,1H),2.28–2.09(m,4H) ,2.04–1.89(m,2H),1.87–1.75(m,1H),1.21–1.15(m,2H),1.13–1.05(m,2H).

Example 142

4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine

The title compound was prepared from 4-chloro-6-(methoxymethyl)pyrimidin-2-amine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C20H21FN6O2 : _396.17 ; m/z found: 397.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.51–8.45(m,1H),8.06(d,J=1.5,1H),7.81–7.74(m,1H),7.20(d,J=8.3,1H), 6.37(s,1H),5.00(s,2H),4.70(s,2H),4.34(s,2H),3.66–3.53(m,1H),3.47(s,3H),2.30–2.07(m, 4H), 2.04–1.90(m,1H), 1.87–1.74(m,1H).

Example 143

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-6-chloropyrimidin-2-amine

The title compound was prepared from 2-amino-4,6-dichloropyrimidine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C18H16ClFN6O : _386.10 ; m/z found: _387.0 [M+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.30–8.23(m,2H),7.77(m,1H),7.23(d,J=8.2,1H),6.29(d,J=2.6,1H),3.64– 3.52(m,1H), 2.31–2.21(m,2H), 2.21–2.09(m,2H), 2.08–1.95(m,1H), 1.90–1.78(m,1H).

Example 144

5-{4-cyclobutyl-2-fluoro-3-[(2-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared from 4-chloro-2-phenylpyrimidine by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for C24H20FN5O: _413.16 ; m/z found: _414.1 [ _M +H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.68(d, J=5.7,1H), 8.50–8.46(m,1H), 8.24–8.18(m,2H), 8.09(d,J=1.5,1H), 7.88–7.81(m,1H),7.44–7.33(m,3H),7.26(m,1H),6.86(d,J=5.6,1H),4.71(s,2H),3.63(p,J=8.9 ,1H), 2.25–2.10(m,4H), 1.99–1.88(m,1H), 1.83–1.75(m,1H).

Example 145

5-{4-Cyclobutyl-2-fluoro-3-[(6-phenylpyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared from 4-chloro-6-phenylpyrimidine by heating under microwave irradiation at 80°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for C24H20FN5O: _413.16 ; m/z found: _414.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.82 (d, J=1.0, 1H), 8.52–8.46 (m, 1H), 8.14–8.06 (m, 3H), 7.88–7.80 (m, 1H), 7.58– 7.48(m,3H),7.39(d,J=1.0,1H),7.25(d,J=8.8,1H),4.69(s,2H),3.63(p,J=8.9,1H),2.29–2.10 (m,4H), 2.05–1.89(m,1H), 1.87–1.75(m,1H).

Example 146

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-benzylpyrimidin-4-amine

The title compound was prepared from 6-amino-2-benzyl-4-chloropyrimidine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C25H23FN6O : _{442.19 ;} m/z found: 443.2 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.32(m,1H),8.08(m,1H),7.69(t,J＝7.8,1H),7.37(s,1H),7.30–7.13(m,5H) ,5.62(s,1H),3.90(s,2H),3.63–3.52(m,1H),2.26–2.04(m,4H),2.02–1.88(m,1H),1.85–1.74(m,1H) .

Example 147

5-(4-Cyclobutyl-2-fluoro-3-{[6-(1-methylethyl)pyrimidin-4-yl]oxy}phenyl)pyrazin-2-amine

The title compound was prepared from 4-chloro-6-isopropyl-pyrimidine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C21H22FN5O : _379.18 ; m/z found: _380.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.68(d, J=0.9,1H),8.49–8.43(m,1H),8.08(d,J=1.5,1H),7.84–7.78(m,1H), 7.23(d, J=8.3,1H),6.86(d,J=0.5,1H),4.70(s,2H),3.60(p,J=8.9,1H),3.02(hept,J=6.9,1H) , 2.26–2.08 (m, 4H), 2.04–1.89 (m, 1H), 1.87–1.77 (m, 1H), 1.34 (d, J=6.9, 6H).

Example 148

3-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-1-methyl-5-(trifluoromethyl)-1H-pyrazole- 4-carbonitrile

Using conditions similar to those described in Example 101, 5-Chloro-1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carbonitrile was heated by microwave irradiation at 80 °C for 1 hour Preparation of the title compound. MS (ESI): mass calculated for _C20H16F4N6O : _{432.13 ;} m/z found: 433.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.46(dd, J=2.2,1.6,1H),8.06(d,J=1.5,1H),7.91(m,1H),7.30–7.20(m,1H), 4.76(s,2H),3.95(s,3H),3.74(p,J＝8.8,1H),2.38–2.19(m,4H),2.14–1.99(m,1H),1.98–1.85(m,1H ).

Intermediate C

(2-((2-chloropyrimidin-4-yl)amino)ethyl)carbamate tert-butyl ester

Intermediate D

(2-((4-chloropyrimidin-2-yl)amino)ethyl)carbamate tert-butyl ester

2,4-Dichloropyrimidine (1.0 g, 6.7 mmol), tert-butyl N-(2-aminoethyl)carbamate (1.06 mL, 6.71 mmol) and triethylamine (1.12 mL, 8.05 mmol) were partially dissolved in acetonitrile (22.5 mL). The mixture was stirred at room temperature for 14 hours, then diluted with water and extracted with DCM. The DCM extracts _were dried over _Na2SO4 , filtered and concentrated to dryness. Purification of the crude mixture by FCC afforded (2-((2-chloropyrimidin-4-yl)amino)ethyl)carbamate tert-butyl ester (1.07 g, 58%) and (2-((4-chloropyrimidin-2 -yl)amino)ethyl)tert-butyl carbamate (280 mg, 15%).

Example 149

[2-({2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-yl}amino)ethyl]carbamate tert-butyl ester

The title compound was prepared from Intermediate C using conditions similar to those described in Example 101 by heating under microwave irradiation at 80°C for 1 hour. MS (ESI): mass calculated for _C25H30FN7O3 : _495.24 ; _m /z found: _496.2 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.43(s, 1H), 8.14(d, J=5.6, 1H), 8.07(s, 1H), 7.73(m, 1H), 7.19(d, J=8.3, 1H), 6.20(d, J=5.6, 1H), 5.51(s, 1H), 5.03(s, 1H), 4.81(s, 2H), 3.66–3.53(m, 1H), 3.25(d, J= 52.0,4H), 2.31–2.05(m,4H), 2.05–1.89(m,1H), 1.87–1.72(m,1H), 1.39(s,9H).

Instance 150

N-{4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-yl}ethane-1,2-diamine

The title compound was prepared from Intermediate D using conditions similar to those described in Example 101 by heating under microwave irradiation at 80°C for 1 hour. MS (ESI): mass calculated for _C20H22FN7O : _395.19 ; m/z found: _396.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.30–8.25 (m, 1H), 8.05 (d, J = 1.5, 1H), 7.84 (s, 1H), 7.67 (m, 1H), 7.25 (d, J =8.2,1H),6.25(d,J=5.8,1H),3.66(p,J=8.9,1H),3.26(t,J=6.2,2H),2.70(s,2H),2.29–2.09( m,4H), 2.06–1.93(m,1H), 1.88–1.77(m,1H).

Example 151

Methyl 2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylate trifluoroacetate

The title compound was prepared from methyl 2-chloropyrimidine-4-carboxylate (280 mg, 15%) by heating under microwave irradiation at 80°C for 2 hours using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C20H18FN5O3 : _395.14 ; m/z found: _396.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.79(d, J=4.9,1H), 8.37(d, J=1.3,1H), 8.11(d, J=1.2,1H), 7.86(m,1H), 7.80(d,J=4.9,1H),7.30–7.24(m,1H),4.67(s,2H),4.04(s,3H),3.76–3.63(m,1H),2.27–2.07(m,4H ), 2.04–1.88(m,1H), 1.87–1.74(m,1H).

Example 152

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylic acid

Obtained as an additional product in the formation of methyl 2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxylate (Example 151) title compound. MS (ESI): mass calculated for _C19H16FN5O3 : _381.12 ; _m /z found: _382.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.78 (d, J = 4.9, 1H), 8.25 (d, J = 1.5, 1H), 8.21 (m, 1H), 7.85–7.79 (m, 2H), 7.30 (d,J=8.3,1H), 3.73–3.61(m,1H), 2.24–2.08(m,4H), 2.06–1.91(m,1H), 1.86–1.75(m,1H).

Example 153

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzoic acid

Starting from Example 103, the title compound was prepared using similar conditions as described in Example 85. MS (ESI): mass calculated for C ₂₁ H ₁₈ FN ₃ O ₃ : 379.13; m/z found: 380.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.24(s,1H),8.16(s,1H),8.03–7.97(m,2H),7.78(m,1H),7.35(d,J＝8.3,1H ), 6.92 (d, J=8.8, 2H), 3.69–3.57 (m, 1H), 2.24–2.11 (m, 4H), 2.04–1.90 (m, 1H), 1.88–1.76 (m, 1H).

Example 154

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridine-3-carboxylic acid

Starting from Example 107, the title compound was prepared using similar conditions as described in Example 85. MS (ESI): mass calculated for _C20H17FN4O3 : _380.13 ; _m /z found: 381.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.59–8.53(m,1H), 8.27(dd,J=8.6,2.4,1H),8.21–8.16(m,1H),7.98(d,J=1.5 ,1H), 7.67(m,1H), 7.26–7.17(m,2H), 2.08–1.95(m,4H), 1.90–1.76(m,1H), 1.73–1.61(m,1H).

Example 155

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzamide

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]benzonitrile (30 mg, 0.083 mmol) was dissolved in TFA (0.75 mL) and washed with concentrated Treated with _{H2SO4 (} 0.25 mL). The mixture was stirred at room temperature for 20 hours. The mixture was then poured onto ice water (100 mL), and the aqueous layer was extracted with 10% MeOH/DCM. The aqueous layer was adjusted to pH 7 with aqueous NaOH and re-extracted with 10% MeOH/DCM. The combined organic extracts were dried and concentrated to dryness. The crude product was purified by FCC to afford the title compound (28 mg, 89%). MS (ESI): mass calculated for _C21H19FN4O2 : _378.15 ; m/z found: 379.2 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, CD ₃ OD) δ8.26(s, 1H), 8.05(s, 1H), 7.89–7.83(m, 2H), 7.77–7.70(m, 1H), 7.33(d, J＝8.3 ,1H), 6.94–6.87(m,2H), 3.69–3.57(m,1H), 2.24–2.10(m,4H), 2.04–1.89(m,1H), 1.87–1.76(m,1H).

Example 156

N'-{4-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-yl}-N,N-dimethylethane -1,2-diamine hydrochloride

5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine (77 mg, 0.21 mmol) was partially dissolved in N, N-dimethylethylenediamine (0.23 mL) and heated at 120° C. for 2 hours by microwave irradiation. The reaction mixture was subjected to direct HPLC purification. The HPLC-worked material was then subjected to FCC to afford the title compound. The final product was converted to the HCl salt by dissolving it in MeOH and treating the solution with aqueous HCl (1.0 M, 0.42 mL). The reaction mixture was then concentrated to dryness to afford the title compound (13 mg, 13%). MS (ESI): mass calculated for _C22H26FN7O : _423.22 ; m/z found: _424.2 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.50-8.45 (m, 1H), 8.06 (d, J=1.5, 1H), 7.93 (s, 1H), 7.79-7.71 (m, 1H), 7.20 (d, J=8.3,1H),6.08(d,J=5.9,1H),5.74(s,1H),4.69(s,2H),3.78-3.65(m,1H),3.37(s,2H),2.51( t,J=5.9,2H), 2.30-2.07(m,11H), 2.04-1.88(m,1H), 1.86-1.73(m,1H).

Example 157

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxamide

The title compound was prepared from Intermediate B and 2-chloropyrimidine-4-carboxamide using conditions similar to those described in Example 160, heating at 80°C for 2 hours. MS (ESI): mass calculated for _C19H17FN6O2 : _{380.14 ;} m/z found: 381.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.84–8.78(d,J=4.9,1H),8.30–8.21(m,2H),8.06–7.97(d,J=1.5,2H),7.80–7.71 (m,2H),7.35–7.28(d,J＝8.3,1H),6.78–6.66(s,2H),3.64–3.51(m,1H),2.16–2.01(m,4H),1.98–1.84( m, 1H), 1.81–1.66 (m, 1H).

Example 158

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-5-amine

The title compound was prepared from Intermediate B and 5-amino-2-chloropyrimidine using conditions similar to those described in Example 164, heating at 140°C for 18 hours. MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.17–8.13 (m, 1H), 7.95 (d, J=1.5, 1H), 7.92 (s, 2H), 7.62–7.54 (m, 1H), 7.15 (d , J=8.3,1H), 3.61–3.49(m,1H), 2.16–1.98(m,4H), 1.96–1.80(m,1H), 1.77–1.63(m,1H).

Example 159

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyrimidin-2-amine

The title compound was prepared using similar conditions as described in Step D of Intermediate A from (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 2-amino-5-bromopyrimidine. MS (ESI): mass calculated for _C15H16FN3O : _273.13 ; _m /z found: 274.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.48 (d, J = 1.4, 2H), 7.10 (d, J = 8.2, 1H), 7.08–6.99 (m, 1H), 5.24 (s, 2H), 3.90 ( d,J=1.4,3H), 3.88–3.74(m,1H), 2.41–2.31(m,2H), 2.22–1.99(m,3H), 1.93–1.82(m,1H).

Intermediate E

3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol

To a 200 mL flask was added a stir bar, 5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrimidin-2-amine (729 mg, 2.7 mmol) and anhydrous DCM (27 mL). The flask was purged with nitrogen, stirred until homogeneous and cooled to -78°C. To the resulting solution was added boron tribromide (1.0 M in DCM, 8.09 mL). The mixture was kept at -78°C for 30 min and then allowed to warm to room temperature. After 5 h, the reaction mixture was poured into a 500 mL mixture of ice and saturated NaHCO ₃ . The mixture was partitioned between EtOAc and the aqueous layer. The EtOAc layer was separated, dried and concentrated to dryness. The resulting solid was purified by FCC to afford the title compound (602 mg, 87%). MS (ESI): mass calculated for _C14H14FN3O : _259.11 ; _m /z found: 260.1 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ9.41(d, J=2.0,1H), 8.39(d, J=1.4,2H), 7.04(d, J=8.0,1H), 6.89(m,1H ), 6.83(s,2H), 3.80–3.65(m,1H), 2.34–2.20(m,2H), 2.15–1.89(m,3H), 1.89–1.74(m,1H).

Instance 160

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

Into a 5 mL vial equipped with a stir bar, 3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol (80 mg, 0.31 mmol) and 2-chloropyrimidine (41 mg, 0.34 mmol) Cs ₂ CO ₃ (203 mg, 0.62 mmol) and DMSO (0.8 mL) were added. The resulting mixture was stirred at 120 °C for about 1 hour by microwave irradiation. The reaction mixture was cooled to room temperature, then the mixture was passed through a syringe filter, and the filtrate was subjected to FCC to give the title compound (81 mg, 78%). MS (ESI): mass calculated for _C18H16FN5O : _337.13 ; m/z found: _338.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.57(d, J=4.8,2H), 8.50(d, J=1.0,2H), 7.31–7.19(m,2H), 7.09–7.05(m,1H), 5.40 (s, 2H), 3.71 (p, J = 8.9, 1H), 2.28–2.07 (m, 4H), 2.03–1.89 (m, 1H), 1.86–1.74 (m, 1H).

Example 161

5-{3-[(4-aminopyrimidin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared from 4-amino-2-chloropyrimidine using conditions similar to those described in Example 160 using DMF as solvent and heating by microwave irradiation for 2 hours. MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.50 (d, J = 1.3, 2H), 8.01 (d, J = 5.7, 1H), 7.25-7.16 (m, 2H), 6.17 (d, J = 5.7, 1H ),5.17(s,2H),5.05(s,2H),3.77-3.64(m,1H),2.33-2.07(m,4H),2.04-1.90(m,1H),1.87-1.74(m,1H ).

Example 162

4-[3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl)pyrimidin-2-amine

The title compound was prepared from 4-chloro-6-(methoxymethyl)pyrimidin-2-amine by heating under microwave irradiation for 2 hours using conditions similar to those described in Example 160. MS (ESI): mass calculated for _C20H21FN6O2 : _396.17 ; m/z found: 397.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.48 (d, J = 1.0, 2H), 7.25–7.15 (m, 2H), 6.38 (s, 1H), 5.30 (s, 2H), 5.08 (s, 2H) , 4.35(s,2H), 3.66–3.53(m,1H), 3.48(s,3H), 2.29–2.06(m,4H), 2.05–1.89(m,1H).

Example 163

5-{4-cyclobutyl-2-fluoro-3-[(4-methylpyrimidin-2-yl)oxy]phenyl}pyrimidin-2-amine

The title compound was prepared from 2-chloro-4-methylpyrimidine using conditions similar to those described in Example 160, heating to 80°C on a hot plate for 3 hours. MS (ESI): mass calculated for _C19H18FN5O : _351.15 ; m/z found: _352.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.50 (d, J = 1.3, 2H), 8.33 (d, J = 5.0, 1H), 7.26–7.18 (m, 2H), 6.92 (d, J = 5.0, 1H ),5.29(s,2H),3.71(p,J=8.9,1H),2.52(s,3H),2.27–2.07(m,4H),2.02–1.90(m,1H),1.85–1.73(m ,1H).

Instance 164

5-{3-[(6-aminopyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrimidin-2-amine

Add a stir bar, 3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenol (88mg, 0.34mmol) and 4-amino-6-chloropyrimidine (46mg, 0.36mmol) K ₂ CO ₃ (70 mg, 0.51 mmol), 18-crown-6 (9 mg, 0.03 mmol) and DMA (0.68 mL) were added to a 5 mL vial. The resulting mixture was stirred at 120 °C for about 3 hours, then cooled to room temperature, passed through a syringe filter, and the filtrate was subjected to FCC to afford the title compound (42 mg, 35%). MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.49 (d, J = 1.1, 2H), 8.23 (s, 1H), 7.26–7.16 (m, 2H), 5.99 (s, 1H), 5.25 (s, 2H) , 5.01 (s, 2H), 3.61 (p, J=8.9, 1H), 2.31–2.08 (m, 4H), 2.00–1.90 (m, 1H), 1.89–1.78 (m, 1H).

Example 165

5-(4-Cyclobutyl-2-fluoro-3-{[4-(1-methylethyl)pyrimidin-2-yl]oxy}phenyl)pyrimidin-2-amine

The title compound was prepared from 2-chloro-4-isopropyl-pyrimidine using conditions similar to those described in Example 160, heating to 80°C for 3 hours. MS (ESI): mass calculated for _C21H22FN5O : _379.180 ; m/z found: _380.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.49(d, J=1.3,2H), 8.38(d, J=5.1,1H), 7.26–7.18(m,2H), 6.92(d, J=5.1,1H ),5.19(s,2H),3.79–3.66(m,1H),3.03–2.92(m,1H),2.27–2.06(m,4H),2.03–1.89(m,1H),1.85–1.74(m , 1H), 1.28 (d, J=6.9, 6H).

Example 166

4-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-2-amine

Using conditions similar to those described in Example 164, the reaction was heated for 18 hours to prepare the title compound from 2-amino-4-chloropyrimidine. MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.50(d, J=1.2,2H), 8.16(d, J=5.6,1H), 7.24(d, J=7.1,1H), 7.19(d, J=8.2 ,1H),6.27(d,J=5.7,1H),5.19(s,2H),4.98(s,2H),3.65–3.54(m,1H),2.29–2.07(m,4H),2.04–1.91 (m,1H),1.88–1.76(m,1H).

Example 167

5-{4-cyclobutyl-3-[(4,6-dimethylpyrimidin-2-yl)oxy]-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared from 2-chloro-4,6-dimethylpyrimidine using conditions similar to those described in Example 160, heating to 80°C for 3 hours. MS (ESI): mass calculated for _C20H20FN5O : _365.17 ; m/z found: 366.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.50 (d, J=1.1, 2H), 7.25–7.16 (m, 2H), 6.76 (s, 1H), 5.19 (s, 2H), 3.77–3.65 (m, 1H), 2.39(s,6H), 2.27–2.06(m,4H), 2.01–1.88(m,1H), 1.85–1.75(m,1H).

Example 168

4-(3-(2-aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy)-6-isopropylpyrimidin-2-amine

Using conditions similar to those described in Example 164, the reaction was heated for 18 hours from 2-amino-4-chloro-6-isopropylpyrimidine to prepare the title compound. MS (ESI): mass calculated for _C21H23FN6O : _394.19 ; m/z found: _395.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.45(s, 1H), 8.04(s, 1H), 7.76(m, 1H), 7.20(d, J=8.2Hz, 1H), 6.12(s, 1H), 5.03(s,2H),4.75(s,2H),3.60(p,J＝8.8,1H),2.85–2.71(m,1H),2.30–2.06(m,4H),2.05–1.90(m,1H ), 1.89–1.74 (m, 1H), 1.24 (d, J=6.9, 6H).

Example 169

2-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carboxamide

The title compound was prepared from 2-chloropyrimidine-4-carboxamide using conditions similar to those described in Example 160 by heating under microwave irradiation at 80°C for 2 hours. MS (ESI): mass calculated for _C19H17FN6O2 : _{380.14 ;} m/z found: 381.0 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.81(d, J=4.9,1H),8.44(s,2H),8.21(s,1H),7.98(s,1H),7.77(d,J= 4.9,1H),7.52–7.42(m,1H),7.30(d,J＝8.2,1H),6.89(s,2H),3.63–3.51(m,1H),2.15–2.00(m,4H), 1.99–1.84(m,1H),1.81–1.68(m,1H).

Instance 170

5-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amine trifluoroacetate

Using conditions similar to those described in Example 164, the title compound was prepared from 6-chloro-4-pyrimidinylmethyl ether by heating the reaction at 140°C for 18 hours. (4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amine trifluoroacetate and 6 -[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol trifluoroacetate (Example 171). MS (ESI): mass calculated for _C19H18FN5O2 : _367.14 ; m/z found: _368.1 [M ₊ H] ⁺ . ¹ H NMR (400MHz, DMSO-d ₆ ) δ8.41-8.36 (d, J = 1.2, 2H), 8.33-8.26 (s, 1H), 7.44-7.34 (m, 1H), 7.26-7.17 (d, J ＝8.1,1H),7.03-6.88(s,1H),5.73-5.67(s,1H),3.54-3.39(m,1H),2.18-1.96(m,4H),1.95-1.82(m,1H) ,1.76-1.64(m,1H),3.32-3.26(m,3H).

Example 171

6-[3-(2-Aminopyrimidin-5-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidin-4-ol trifluoroacetate

Formed as additional product upon formation of 5-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyrimidin-2-amine (Example 170) . MS (ESI): mass calculated for _C18H16FN5O2 : _353.13 ; m/z found: _354.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ12.60(s,1H), 8.42(d, J=1.2,2H), 8.07–8.01(m,1H), 7.42–7.34(m,1H), 7.20( d,J＝8.2,1H),7.18–6.94(m,2H),5.62(s,1H),3.54–3.39(m,1H),2.19–1.96(m,4H),1.96–1.81(m,1H ), 1.77–1.64(m,1H).

Example 172

6-Amino-3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile

Using similar conditions to those described in step D of intermediate A with (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 2-amino-5-bromo-6-cyanopyrazine Preparation of the title compound. MS (ESI): mass calculated for _C16H15FN4O : _298.12 ; m/z found: 299.1 [M ₊ H] ⁺ . ¹ HNMR (600MHz, CDCl ₃ )δ8.21(s,1H),7.21–7.16(m,1H),7.16–7.10(m,1H),3.86–3.76(m,1H),2.39–2.30(m, 2H), 2.21–2.09(m,2H), 2.09–1.98(m,1H), 1.91–1.81(m,1H).

Example 173

6-Amino-3-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile

Using similar conditions as described for Intermediate B, the title compound was prepared from 6-amino-3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile. MS (ESI): mass calculated for _C15H13FN4O : _284.11 ; m/z found: 285.1 [M ₊ H] ⁺ . ¹ HNMR (600MHz, CD ₃ OD) δ8.17(s,1H),7.13–7.07(m,1H),6.95–6.90(dd,J＝8.0,6.8,1H),3.89–3.79(m,1H) ,2.43–2.33(m,2H),2.25–2.14(m,2H),2.13–2.01(m,1H),1.92–1.83(m,1H).

Example 174

3-{[3-(5-Amino-3-cyanopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}benzoic acid

Using similar conditions as described in Example 1, 6-amino-3-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile and 3-(bromomethyl)benzene Methyl formate to prepare the title compound. MS (ESI): mass calculated for _C23H19FN4O3 : _418.14 ; _m /z found: _419.1 [M+H] ⁺ . ¹ H NMR (600MHz,DMSO-d ₆ )δ8.22(s,1H),8.09–8.05(m,1H),7.96–7.91(m,1H),7.73–7.68(m,1H),7.57–7.52( m,1H),7.36(s,2H),7.33–7.26(m,2H),5.09(s,2H),3.80–3.70(p,J=9.0,1H),2.26–2.15(m,2H), 2.15–2.04(m,2H),1.99–1.88(m,1H),1.84–1.73(m,1H).

Example 175

2-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine

Using similar conditions as described in Intermediate A, Step D, the title was prepared from (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 5-bromo-4,7-diazaindole compound. MS (ESI): mass calculated for C17H16FN3O: _297.13 ; m/z found: _298.1 [ _M +H] ⁺ . ¹ HNMR (600MHz, CDCl ₃ )δ9.43–9.28(s,1H),8.72–8.67(d,J＝2.6,1H),7.67–7.58(m,2H),7.19–7.13(m,1H), 6.82–6.78(dd, J=3.7,1.9,1H), 3.96–3.89(d,J=1.3,3H), 3.89–3.77(m,1H), 2.42–2.32(m,2H), 2.21–2.11( m,2H), 2.10–1.99(m,1H), 1.92–1.83(m,1H).

Example 176

6-Cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol

Prepared using similar conditions as described in Intermediate B starting from 2-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-5H-pyrrolo[2,3-b]pyrazine title compound. MS (ESI): mass calculated for _C16H14FN3O : _283.11 ; _m /z found: 284.0 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ9.16(s, 1H), 8.67(d, J=2.6, 1H), 7.69–7.61(m, 1H), 7.49–7.39(m, 1H), 7.14(d, J＝8.1,1H),6.84–6.77(m,1H),5.48(s,1H),3.89–3.76(m,1H),2.48–2.34(m,2H),2.30–2.15(m,2H), 2.16–1.99(m,1H),1.96–1.82(m,1H).

Example 177

2-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-5H-pyrrolo[2,3-b]pyrazinetrifluoro Acetate

To a solution equipped with a stir bar, 6-cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol (40mg, 0.14mmol) and 4-(trifluoro To a 5 mL vial of methyl)benzyl bromide (41 mg, 0.17 mmol) was added KOH (24 mg, 0.42 mmol) and 0.78 mL DMSO. The resulting mixture was stirred at room temperature for about 20 hours. The mixture was passed through a syringe filter and the filtrate was subjected to HPLC purification to afford the title compound (12 mg, 15%). MS (ESI): mass calculated for _C24H19F4N3O : _441.15 ; _m /z found: 442.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.95(s, 1H), 8.64(d, J=2.0, 1H), 7.76(dd, J=3.5, 2.7, 1H), 7.74–7.64(m, 3H), 7.61 (d, J = 8.1, 2H), 7.28–7.23 (m, 1H), 6.92 (dd, J = 3.7, 1.9, 1H), 5.14 (s, 2H), 3.82 (p, J = 8.7, 1H) ,2.37–2.26(m,2H),2.25–2.11(m,2H),2.11–1.97(m,1H),1.94–1.79(m,1H).

Example 178

2-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine

Step A :

Using a method similar to that described in Example 216, 2-(3-(benzyloxy)-4-chloro-2-fluorophenyl)-5H was prepared from 5-bromo-4,7-diazaindole - pyrrolo[2,3-b]. MS (ESI): mass calculated for _C19H13ClFN3O : _353.07 ; _m /z found: 354.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ9.35(s, 1H), 8.70(d, J=2.9, 1H), 7.72-7.65(m, 2H), 7.58-7.51(m, 2H), 7.44-7.30( m, 4H), 6.82 (dd, J = 3.7, 1.9, 1H), 5.20 (s, 2H).

Step B :

The title compound was prepared using similar conditions as described in Example 83 from 2-(3-(benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine . MS (ESI): mass calculated for _C23H20FN3O : _373.16 ; m/z found: 374.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ10.09(s,1H),8.66(s,1H),7.76–7.65(m,2H),7.51–7.46(m,2H),7.45–7.33(m,3H) ,7.24(d,J＝8.3,1H),6.88(m,1H),5.09(s,2H),3.88–3.76(m,1H),2.36–2.26(m,2H),2.22–2.09(m, 2H), 2.09–1.95(m,1H), 1.91–1.81(m,1H).

Example 179

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyridin-2-amine hydrochloride

Under nitrogen, solid (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (350 mg, 1.56 mmol), 2-amino-5-bromopyridine (270 mg, 1.56 mmol) and Pd( dppf)Cl ₂ ·CH ₂ Cl ₂ (102 mg, 0.16 mmol) was placed in a round bottom flask. The flask was then filled with bubbled THF (7 mL), KOH (760 mg, 14 mmol) and water (2 mL). The reaction mixture was stirred overnight at room temperature, then treated with EtOAc (20 mL). The mixture was dried, filtered and concentrated to dryness. The residue was subjected to FCC to afford the pure title compound. By dissolving the material in ether (10 mL), followed by the addition of 4M HCl in 1,4-bis Alkanes solution (0.3 mL) converted the material to the hydrochloride salt. The precipitate was collected by filtration, washed with ether and dried to give the title compound (330 mg, 78%). MS (CI): mass calculated for _C16H17FN2O : _272.13 ; m/z found: 273.1 [M ₊ H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ ) δ14.12(s, 1H), 8.31-8.05(m, J=22.9, 5.6, 4H), 7.28-7.19(m, 2H), 7.08(d, J=9.3 ,1H),3.83(d,J=0.8,3H),3.80-3.71(m,1H),2.35-2.25(m,2H),2.16-1.96(m,3H),1.87-1.77(m,J= 18.5, 8.7, 1H).

Intermediate F

5-(4-Cyclobutyl-2-fluoro-3-hydroxyphenyl)pyridin-2-amine

A solution consisting of 5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyridin-2-amine (333 mg, 1.08 mmol) and DCM (10 mL) was cooled to -78 °C and then A solution of 1 MBr ₃ in DCM (3.3 mL, 3.3 mmol) was added for treatment. The solution was kept at -78°C for 30 min, then warmed to room temperature and stirred overnight. The reaction mixture was poured into a beaker with ice and saturated NaHCO ₃ , then extracted with EtOAc. The organic phase was separated, dried and concentrated to dryness to afford the title compound. MS (CI): mass calculated for _C15H15FN2O : _258.12 ; m/z found: 259.2 [M ₊ H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ )δ9.29(d, J=2.0,1H),8.05(s,1H),7.59-7.46(m,1H),7.01(d,J=8.0,1H), 6.82(m,1H),6.52(dd,J=8.6,0.6,1H),6.10(s,2H),3.77-3.66(m,J=8.6,1H),2.32-2.21(m,2H),2.14 -2.02(m,2H),2.02-1.90(m,1H),1.85-1.72(m,1H).

Instance 180

5-Methyl-4-((3-(6-aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)benzoate

5-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyridin-2-amine (50mg, 0.19mmol), Cs ₂ CO ₃ (190mg, 0.58mmol), 4-(bromomethyl) A mixture of methyl benzoate (56 mg, 0.25 mmol) and DMF (1 mL) was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with EtOAc. The organic phase was separated, dried, concentrated to dryness, and the residue was subjected to FCC to afford the title compound (74 mg, 94%). MS (CI): mass calculated for _C24H23FN2O3 : _406.17 ; m/z found: _407.3 [ _M +H] ⁺ . ¹ HNMR (600MHz, DMSO-d ₆ ) δ8.09(s, 1H), 8.05-7.97(m, 2H), 7.62(d, J=8.4, 2H), 7.57(d, J=8.6, 1H), 7.23-7.12(m,2H),6.52(dd,J＝8.6,0.6,1H),6.15(s,2H),5.10(s,2H),3.87(s,3H),3.79-3.67(m,J =8.8,1H), 2.25-2.15(m,2H), 2.14-2.02(m,2H), 2.00-1.89(m,1H), 1.83-1.72(m,J=8.9,8.4,1H).

Example 181

4-((3-(6-aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)benzoic acid

5-Methyl-4-((3-(6-aminopyridin-3-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)-benzoate (54mg, 0.13mmol ), KOH (2M, 0.3 mL), THF (2 mL) and MeOH (1 mL) was stirred at room temperature for 16 h. The mixture was concentrated to dryness, treated with water (2 mL) and HCl (1M, 0.75 mL). The resulting precipitate was collected, washed with water and dried to give the title compound (0.48 mg, 92%). MS (CI): mass calculated for _C23H21FN2O3 : _392.15 ; _m /z found: 393.3 [M ₊ H] ⁺ .

Intermediate F'

5-Bromo-1H-imidazo-[4,5-b]pyrazine

To a 50 mL round bottom flask equipped with a reflux condenser was added 5-bromopyrazine-2,3-diamine (400 mg, 2.1 mmol) and triethyl orthoformate (3.1 g, 21.2 mmol) under nitrogen. The mixture was heated to reflux and stirred for 24h. The reaction was cooled to room temperature, concentrated to dryness, and the residue was purified by HPLC to afford 320 mg (76% yield) of the title compound. MS (ESI): mass calculated for _C5H3BrN4 : _197.95 ; m/z found: 199.1 [M ₊ H] ⁺ .

Example 182

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-imidazo[4,5-b]pyrazine

To 5-bromo-1H-imidazo-[4,5-b]pyrazine (50 mg, 0.25 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid in a microwave vial (67 mg, 0.30 mmol) and [1,1'bis(diphenylphosphine)-ferrocene]palladium(II) dichloride CH ₂ Cl ₂ (10 mg, 0.01 mmol) was added to acetonitrile (2.0 mL) and sodium bicarbonate solution (2.0 mL saturated solution). The reaction was degassed with nitrogen, the vial was capped and irradiated by microwave irradiation at 110 °C for 90 min, then cooled to room temperature. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (25 mL) and brine (25 mL), dried (Na ₂ SO ₄ ) and concentrated to dryness. The crude residue was purified by HPLC to afford the title compound (30 mg, 40%). MS (ESI): mass calculated for _C16H15FN4O : _298.12 ; m/z found: 299.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) is complex due to the existence of multiple configurations on the NMR time scale, and the listed peaks are for identification purposes only: δ11.38(s), 10.85(s), 9.02(d, J＝2.03), 8.91(d, J＝2.10), 8.53(s), 7.87-7.77(m), 7.58-7.49(m), 7.26-7.17(m), 3.96(s), 3.94(s), 3.92-3.80(m), 2.51-2.32(m), 2.30-1.98(m), 1.97-1.78(m).

Example 183

6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3H-imidazo[4,5-b]pyridine

Prepared using a procedure similar to that described in Example 182 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 6-bromo-3H-imidazo[4,5-b]pyridine title compound. MS (ESI): mass calculated for _C17H16FN3O : _297.13 ; _m /z found: 298.2 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ11.41(s,1H),8.62(s,1H),8.30(s,2H),7.22-7.12(m,2H),3.94(s,3H),3.92-3.78 (m,1H), 2.48-2.33(m,2H), 2.29-2.00(m,3H), 1.97-1.79(m,1H).

Example 184

7-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4] Zinc

In a manner similar to that described in Example 1, (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 7-bromo-3,4-dihydro-2H-pyrido[3 ,2-b][1,4] Oxyzine to prepare the title compound. MS (ESI): mass calculated for _C18H19FN2O2 : _314.14 ; m/z found: 315.2 [M ₊ H] ₊ ^{. 1} HNMR (500MHz, CDCl ₃ )δ7.86(s,1H),7.19(s,1H),7.09-7.02(m,2H),5.44(s,1H),4.28-4.19(m,2H),3.89 (s,3H),3.84-3.75(m,1H),3.59(s,2H),2.39-2.31(m,2H),2.20-2.10(m,2H),2.09-2.00(m,1H),1.90 -1.82(m,1H).

Example 185

6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] Azin-7-yl)-2-fluorophenol

7-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4] A solution of oxazine (0.103 g, 0.328 mmol) in _{CH2Cl2 (} 10 mL) was cooled to -78 °C and treated dropwise with _BBr3 (IM in _CH2Cl2 , 1.6 mL ₎ . The reaction mixture was stirred for 16 hours, gradually warming to room temperature. The mixture was concentrated to dryness, and the residue was purified by HPLC to give the title compound (81 mg, 82%). MS (ESI): mass calculated for _C17H17FN2O2 : _300.13 ; m/z found: 301.1 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, CDCl ₃ ) δ7.84(m,1H),7.20(m,1H),7.02(d,J=8.1,1H),6.83(m,1H),4.27-4.23(m,2H) ,3.88-3.74(m,1H),3.63-3.52(m,2H),2.42-2.32(m,2H),2.23-2.10(m,2H),2.08-2.00(m,1H),1.92-1.80( m, 1H).

Example 186

7-[3-(Benzyloxy)-4-cyclobutyl-2-fluorophenyl]-3,4-dihydro-2H-pyrido[3,2-b][1,4] Zinc

In a manner similar to that described in Example 28, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] (Azin-7-yl)-2-fluorophenol and (bromomethyl)benzene to prepare the title compound. MS (ESI): mass calculated for _C24H23FN2O2 : _390.17 ; m/z found: 391.2 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ7.72(s, 1H), 7.64-7.61(m, 1H), 7.47-7.42(m, 2H), 7.41-7.31(m, 3H), 7.23-7.16(m ,2H),5.05(s,2H),4.36(t,J=4.6,2H),3.81-3.73(m,1H),3.73-3.65(m,2H),2.31-2.20(m,2H),2.17 -1.95(m,3H),1.87-1.79(m,1H).

Example 187

3-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] Azin-7-yl)-2-fluorophenoxy]methyl}benzonitrile

In a manner similar to that described in Example 28, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (azin-7-yl)-2-fluorophenol and 3-(bromomethyl)benzonitrile. MS (ESI): mass calculated for _C25H22FN3O2 : _415.17 ; _m /z found: 416.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ7.82(s, 1H), 7.78(d, J=7.8, 1H), 7.74-7.70(m, 2H), 7.68-7.64(m, 1H), 7.59(m ,1H),7.27-7.20(m,2H),5.12(s,2H),4.40-4.33(m,2H),3.84-3.68(m,3H),2.34-2.24(m,2H),2.20-1.97 (m,3H), 1.90-1.81(m,1H).

Example 188

7-(4-Cyclobutyl-2-fluoro-3-{[3-(methylsulfanyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3, 2-b][1,4] Zinc

In a manner similar to that described in Example 28, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (oxazin-7-yl)-2-fluorophenol and 1-(bromomethyl)-3-(methylsulfanyl)benzene. MS (ESI): mass calculated for _C25H25FN2O4S : _468.15 ; m/z found: _469.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.06(s, 1H), 7.94(d, J=7.9, 1H), 7.81(d, J=7.7, 1H), 7.72(s, 1H), 7.70-7.61 (m,2H),7.25-7.19(m,2H),5.18(s,2H),4.38-4.33(m,2H),3.84-3.73(m,1H),3.72-3.67(m,2H),3.12 (s, 3H), 2.34-2.23 (m, 2H), 2.18-1.98 (m, 3H), 1.89-1.79 (m, 1H).

Example 189

7-(4-Cyclobutyl-2-fluoro-3-{[4-(methylsulfanyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3, 2-b][1,4] Zinc

In a manner similar to that described in Example 28, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (oxazin-7-yl)-2-fluorophenol and 1-(bromomethyl)-4-(methylsulfanyl)benzene. MS (ESI): mass calculated for _C25H25FN2O4S : _468.15 ; m/z found: _469.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.02-7.96 (m, 2H), 7.74 (d, J = 8.4, 3H), 7.65-7.62 (m, 1H), 7.27-7.20 (m, 2H), 5.17 (s,2H),4.38-4.34(m,2H),3.87-3.74(m,1H),3.73-3.66(m,2H),3.13(d,J=3.7,3H),2.34-2.24(m, 2H), 2.21-1.98(m, 3H), 1.90-1.80(m, 1H).

Example 190

4-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] Azin-7-yl)-2-fluorophenoxy]methyl}benzonitrile

In a manner similar to that described in Example 28, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (azin-7-yl)-2-fluorophenol and 4-(bromomethyl)benzonitrile. MS (ESI): mass calculated for _C25H22FN3O2 : _415.17 ; m/z found: _416.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ7.80-7.75 (m, 2H), 7.72 (d, J = 0.8, 1H), 7.69-7.61 (m, 3H), 7.26-7.19 (m, 2H), 5.13 (s,2H),4.39-4.31(m,2H),3.86-3.74(m,1H),3.72-3.68(m,2H),2.34-2.23(m,2H),2.21-1.95(m,3H) ,1.90-1.80(m,1H).

Example 191

7-(4-Cyclobutyl-2-fluoro-3-{[4-(trifluoromethyl)benzyl]oxy}phenyl)-3,4-dihydro-2H-pyrido[3,2 -b][1,4] Zinc

In a manner similar to that described in Example 28, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from azin-7-yl)-2-fluorophenol and 1-(bromomethyl)-4-(trifluoromethyl)benzene. MS (ESI): mass calculated for _C25H22F4N2O2 : _458.16 ; m/z found: _459.3 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, CD ₃ OD) δ7.74-7.61(m,6H),7.26-7.19(m,2H),5.14(s,2H),4.39-4.31(m,2H),3.87-3.74(m ,1H), 3.72-3.68(m,2H), 2.33-2.22(m,2H), 2.19-1.97(m,3H), 1.89-1.80(m,1H).

Example 192

3-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] Azin-7-yl)-2-fluorophenoxy]methyl}benzamide

In a manner similar to that described in Example 28, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (oxazin-7-yl)-2-fluorophenol and 3-(bromomethyl)benzamide. MS (ESI): mass calculated for _C25H24FN3O3 : _433.18 ; _m /z found: 434.2 [ _M +H] ⁺ . ¹ HNMR (500MHz, MeOD) δ8.01–7.97(m,1H),7.88–7.83(m,1H),7.74–7.71(m,1H),7.67–7.60(m,2H),7.53–7.47(m ,1H),7.23–7.19(m,2H),5.14–5.10(m,2H),4.38–4.33(m,2H),3.83–3.75(m,1H),3.72–3.67(m,2H),2.32 –2.22 (m, 2H), 2.17 – 2.07 (m, 2H), 2.06 – 1.96 (m, 1H), 1.88 – 1.80 (m, 1H).

Example 193

4-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] Azin-7-yl)-2-fluorophenoxy]methyl}benzamide

In a manner similar to that described in Example 28, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (oxazin-7-yl)-2-fluorophenol and 4-(bromomethyl)benzamide. MS (ESI): mass calculated for _C25H24FN3O3 : _433.18 ; _m /z found: 434.3 [ _M +H] ⁺ . ¹ HNMR (600MHz, CD ₃ OD) δ7.90(d, J=8.3,2H),7.72(s,1H),7.62(d,J=5.3,1H),7.56(d,J=8.3,2H) ,7.23-7.20(m,2H),5.12(s,2H),4.37-4.34(m,2H),3.82-3.76(m,1H),3.72-3.69(m,2H),2.31-2.24(m, 2H), 2.17-2.11(m, 2H), 2.06-1.99(m, 1H), 1.88-1.81(m, 1H).

Example 194

7-(4-cyclobutyl-2-fluoro-3-{[6-(trifluoromethyl)pyridin-2-yl]oxy}phenyl)-3,4-dihydro-2H-pyrido[ 3,2-b][1,4] Zinc

In a manner similar to that described in Example 28, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (oxazin-7-yl)-2-fluorophenol and 2-bromo-6-(trifluoromethyl)pyridine. MS (ESI): mass calculated for _C23H19F4N3O2 : _445.14 ; m/z found: 446.1 [ _{M +} H] ₊ ^{. 1} HNMR (600MHz, CD ₃ OD) δ8.05 (m, 1H), 7.71 (d, J = 1.4, 1H), 7.62-7.59 (m, 1H), 7.51 (d, J = 7.4, 1H), 7.42 (m,1H),7.36-7.30(m,2H),4.37-4.33(m,2H),3.72-3.68(m,2H),3.67-3.61(m,1H),2.22-2.09(m,4H) ,2.03-1.92(m,1H),1.85-1.76(m,1H).

Example 195

(4-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] (oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acetic acid

6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] A solution of azin-7-yl)-2-fluorophenol (50 mg, 0.17 mmol) and 2-(4-(bromomethyl)phenyl)acetic acid (38 mg, 0.17 mmol) in DMSO (1 mL) was treated with tert-butanol Potassium (38mg, 0.33mmol) was treated and stirred at 80°C for 16 hours. The reaction was then cooled to room temperature, filtered, and the filtrate directly subjected to HPLC purification to give (4-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b] [1,4] (oxazin-7-yl)-2-fluorophenoxy]methyl}phenyl)acetic acid (8 mg, 9%). MS (ESI): mass calculated for _C26H25FN2O4 : _448.18 ; m/z found: 449.2 [M ₊ H] ₊ ^{. 1} HNMR (600MHz, CD ₃ OD) δ7.72(s, 1H), 7.60(s, 1H), 7.40(d, J=8.1, 2H), 7.31(d, J=8.1, 2H), 7.19(d ,J=6.0,2H),5.04(s,2H),4.38-4.32(m,2H),3.78-3.72(m,1H),3.71-3.67(m,2H),3.63(s,2H),2.29 -2.22 (m, 2H), 2.16-2.07 (m, 2H), 2.04-1.97 (m, 1H), 1.84 (t, J=9.6, 1H).

Example 196

4-{[6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] Azin-7-yl)-2-fluorophenoxy]methyl}benzoic acid

In a manner similar to that described in Example 195, via 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] Preparation by reaction of oxazin-7-yl)-2-fluorophenol and 4-(bromomethyl)benzoic acid. MS (ESI): mass calculated for _C25H23FN2O4 : _434.16 ; m/z found: 435.1 [M ₊ H] ₊ ^{. 1} HNMR (600MHz, CD ₃ OD) δ8.07-8.03 (m, 2H), 7.73 (d, J = 1.3, 1H), 7.66-7.64 (m, 1H), 7.57 (d, J = 8.4, 2H) ,7.22(d,J=4.4,2H),5.13(s,2H),4.368-4.35(m,2H),3.83-3.76(m,1H),3.74-3.69(m,2H),2.31-2.25( m, 2H), 2.17-2.09(m, 2H), 2.06-1.98(m, 1H), 1.88-1.81(m, 1H).

Example 197

3-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine

In a manner similar to that described in Example 1, with (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 3-chloro-7H-pyrrolo[2,3-c]pyridazine Preparation of the title compound. MS (ESI): mass calculated for C17H16FN3O: _297.13 ; m/z found: _298.1 [ _M +H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ12.05(s, 1H), 8.15(d, J=2.2, 1H), 7.80(d, J=3.4, 1H), 7.71(m, 1H), 7.21(d, J=8.1,1H),6.61(d,J=3.4,1H),3.94(d,J=1.2,3H),2.44-2.35(m,2H),2.25-2.14(m,2H),2.13-2.05 (m, 1H), 1.81 (d, J = 7.1, 2H).

Example 198

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine

Will be loaded with 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (0.5g, 2.5mmol), (4-cyclobutyl-2-fluoro-3-methoxy Phenyl)boronic acid (0.563g, 2.51mmol), potassium carbonate (1.041g, 7.54mmol) and [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) _CH2 The reaction flask of Cl2 (0.093 _g , 0.13 mmol) was sealed and the atmosphere was exchanged with _N2 (3x). The flask was filled with DMF (2 mL), toluene (5 mL) and deionized _H2O (5 mL) immediately after bubbling. The mixture was heated at 80°C for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), and washed with brine (3 x 50 mL). The organic layer was separated, dried over _MgSO4 , filtered and concentrated to dryness. The residue was purified by FCC to afford the title compound (0.605 g, 81%). MS (ESI): mass calculated for _C18H19FN2O : 298.15; m/z found: _299.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ7.98(d, J=0.9Hz, 1H), 7.44(s, 1H), 7.09-7.01(m, 2H), 4.62(s, 1H), 3.89(d, J ＝1.3Hz, 3H), 3.85-3.74(m, 1H), 3.72-3.63(m, 2H), 3.12(t, J＝8.4Hz, 2H), 2.41-2.30(m, 2H), 2.22-1.99( m,3H), 1.95-1.81(m,1H).

Example 199

6-cyclobutyl-3-(2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-fluorophenol

In a manner similar to that described in Example 185, via 5-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-2,3-dihydro-1H-pyrrolo[2,3- b] Reactive preparation of pyridines. MS (ESI): mass calculated for _C17H17FN2O : _284.13 ; m/z found: _285.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ7.82-7.76 (m, 1H), 7.64 (s, 1H), 7.06 (d, J = 8.0, 1H), 6.86 (m, 1H), 3.95 (t, J ＝8.3,2H),3.85-3.72(m,1H),3.30-3.22(m,2H),2.41-2.29(m,2H),2.21-1.99(m,3H),1.90-1.81(m,1H) .

Intermediate G

3-(5-aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenol

Step A :

Add a stir bar, 2-(1,1-dimethylethyl)-6-fluorophenol (2.62 g, 15.6 mmol), tert-butyldimethylsilyl chloride (4.84 g, 31.1 mmol) into a 100 mL round bottom flask ), imidazole (1.46g, 21.5mmol) and anhydrous DMF (48mL). The flask was purged with nitrogen and heated at 60°C for 24 hours. The mixture was cooled to room temperature, then partitioned between EtOAc and water. The EtOAc layer was washed with water, then brine. The organic layer was dried _{over Na2SO4} and concentrated. Purification by FCC afforded tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (4.2 g, 96%). ¹ HNMR (600MHz, CDCl ₃ )δ7.04(m,1H),6.92(m,1H),6.77(m,1H),1.56(s,6H),1.39(s,9H),1.01(d,J =0.7,9H).

Step B :

To a 100 mL round bottom flask was added a stir bar, anhydrous THF (15.0 mL) and 2,2,6,6-tetramethylpiperidine (2.3 mL, 13.6 mmol). The flask was cooled to -78 °C (bath temperature) and then treated with 2.5M n-BuLi in hexane (5.46 mL, 13.6 mmol) for 2 min. The resulting mixture was stirred for 5 min, then allowed to warm to 0 °C. After 65 min, the mixture was recooled to -78 °C and treated with B(O-iPr) ₃ (17.5 mL, 13.6 mmol) for 4 min. After 20 min, a solution consisting of tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (2.57 g, 9.1 mmol) and anhydrous THF (5.0 mL) was added over 2 min and Stirring was continued for 3 hours. The reaction was allowed to gradually warm to room temperature while stirring for 18 hours, then HOAc (5.2 mL, 91 mmol) was added. The mixture was then poured into water and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (200 mL), the extract was dried _{over Na2SO4} , filtered and concentrated to dryness. Purification by FCC afforded (4-(tert-butyl)-3-((tert-butyldimethylsilyl)oxy)-2-fluorophenyl)boronic acid (2.13 g, 72%).

Step C :

In a similar manner to Intermediate A, Step D, (4-(tert-butyl)-3-((tert-butyldimethylsilyl)oxy)-2-fluorophenyl)boronic acid was coupled to 2 -Amino-5-bromopyrazine to give the title compound (658 mg, 78%). MS (ESI): mass calculated for C14H16FN3O: _261.13 ; m/z found: _262.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ9.38(d, J=3.2,1H), 8.21(dd, J=2.3,1.5,1H), 7.93(d, J=1.5,1H), 7.11(m , 1H), 6.98 (d, J=8.4, 1H), 6.56 (s, 2H), 1.32 (s, 9H).

Instance 200

5-(4-tert-butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrazin-2-amine

The title compound was formed as an additional product generated in step C of the synthesis of Intermediate E (56 mg, 5%). MS (ESI): mass calculated for C20H30FN3OSi: _375.21 ; m/z found: _376.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47–8.40(m,1H),8.09(d,J=1.4,1H),7.35–7.28(m,1H),7.13(dd,J=8.5,1.5,1H ), 4.62 (s, 2H), 1.41 (s, 9H), 1.02 (d, J=0.7, 9H), 0.34 (d, J=4.3, 6H).

instance 201

5-[4-tert-butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

Intermediate G was used to prepare the title compound using conditions similar to those described in Example 160, heating at 120°C for 4 hours. MS (ESI): mass calculated for _C18H18FN5O : _339.15 ; m/z found: _340.0 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.69(d, J=4.8,2H),8.22(s,1H),8.00(d,J=1.4,1H),7.71–7.62(m,1H), 7.35–7.26 (m, 2H), 6.68 (s, 2H), 1.30 (s, 9H).

instance 202

6-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared from Intermediate G and 4-amino-6-chloropyrimidine using conditions similar to those described in Example 164, heating at 120°C for 5 hours. MS (ESI): mass calculated for _C18H19FN6O : _{354.16 ;} m/z found: 355.1 [M+H] ⁺ . ¹ HNMR (400MHz,DMSO-d ₆ )δ8.23(s,1H),8.08–7.99(m,2H),7.65(m,1H),7.29(d,J＝8.6,1H),6.92(s, 2H), 6.71(s, 2H), 5.94(s, 1H), 1.30(s, 9H).

Example 203

2-[3-(5-Aminopyrazin-2-yl)-6-tert-butyl-2-fluorophenoxy]pyrimidin-4-amine

The title compound was prepared from Intermediate G and 4-amino-2-chloropyrimidine using conditions similar to those described in Example 164, heating at 140°C for 15 hours. MS (ESI): mass calculated for _C18H19FN6O : _{354.16 ;} m/z found: 355.0 [M+H] ⁺ . ¹ H NMR (600MHz, CD ₃ OD) δ8.25 (s, 1H), 8.04 (d, J = 1.4, 1H), 7.88 (d, J = 5.9, 1H), 7.66–7.59 (m, 1H), 7.30 (dd, J = 8.6, 1.2, 1H), 6.24 (d, J = 5.9, 1H), 1.37 (s, 9H).

instance 204

5-{4-tert-butyl-2-fluoro-3-[(6-methoxypyrimidin-4-yl)oxy]phenyl}pyrazin-2-amine

The title compound was prepared from Intermediate G and 6-chloro-4-pyrimidinylmethyl ether using conditions similar to those described in Example 164, heating at 120 °C for 3 hours, to afford the title compound and Example 205. MS (ESI): mass calculated for _C19H20FN5O2 : _369.16 ; m/z found: _370.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.46–8.42 (m, 1H), 8.08 (d, J=1.5, 1H), 7.98 (s, 1H), 7.78–7.69 (m, 1H), 7.32–7.27 ( m,1H), 5.90(s,1H), 4.67(s,2H), 3.51(s,3H), 1.37(s,9H).

instance 205

5-(4-tert-butyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

The title compound was formed as an additional product of Preparative Example 204. MS (ESI): mass calculated for _C15H18FN3O : _275.14 ; _m /z found: 276.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.50–8.45 (m, 1H), 8.09 (d, J=1.5, 1H), 7.48–7.40 (m, 1H), 7.17–7.09 (m, 1H), 4.64 ( s, 2H), 3.99 (d, J=2.2, 3H), 1.40 (s, 9H).

Intermediate H

3-(2-aminopyrimidin-5-yl)-6-tert-butyl-2-fluorophenol

The title compound was prepared in Step C from 2-amino-5-bromopyrimidine using conditions similar to those described for Intermediate E. MS (ESI): mass calculated for _C14H16FN3O : _261.13 ; _m /z found: 262.0 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ9.48(s, 1H), 8.39(d, J＝1.5, 2H), 7.02(dd, J＝8.3, 1.3, 1H), 6.89–6.76(m, 3H ), 1.37(s,9H).

Instance 206

5-(4-tert-butyl-3-{[tert-butyl(dimethyl)silyl]oxy}-2-fluorophenyl)pyrimidin-2-amine

Formed as an additional product of step C during the formation of intermediate F. MS (ESI): Mass calculated for _C20H30FN3OSi : _375.21 ; m/z found: 376.0 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.53–8.40(m,2H),7.15–7.08(m,1H),6.87–6.77(m,1H),5.22(s,2H),1.41(s,9H) , 1.01 (s, 9H), 0.33 (d, J = 4.2, 6H).

Instance 207

5-[4-tert-butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

Intermediate H was used to prepare the title compound using conditions similar to those described in Example 160, heating at 120°C for 2 hours. MS (ESI): mass calculated for _C18H18FN5O : _339.15 ; m/z found: _340.0 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.68(d, J=4.8,2H), 8.41(d, J=1.4,2H), 7.43–7.35(m,1H), 7.35–7.25(m,2H ), 6.88(s,2H), 1.30(s,9H).

Instance 208

5-{3-[(6-aminopyrimidin-4-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared from Intermediate H and 4-amino-6-chloropyrimidine using conditions similar to those described in Example 164, heating at 140°C for 15 hours. MS (ESI): mass calculated for _C18H19FN6O : _{354.16 ;} m/z found: 355.0 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.41(d, J=1.0,2H),8.04(s,1H),7.41–7.32(m,1H),7.27(d,J=8.4,1H), 6.89 (d, J=4.5, 4H), 5.97–5.89 (m, 1H), 1.30 (s, 9H).

Example 209

5-{3-[(4-aminopyrimidin-2-yl)oxy]-4-tert-butyl-2-fluorophenyl}pyrimidin-2-amine

The title compound was prepared from Intermediate H and 4-amino-2-chloropyrimidine using conditions similar to those described in Example 164, heating at 140°C for 13 hours. MS (ESI): mass calculated for _C18H19FN6O : _{354.16 ;} m/z found: 355.0 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.46 (d, J=1.2, 2H), 8.02 (d, J=5.7, 1H), 7.29-7.24 (m, 1H), 7.18-7.09 (m, 1H), 6.12 (d, J = 5.7, 1H), 4.98 (s, 2H), 4.80 (s, 2H), 1.40 (s, 9H).

Example 210

5-(4-Bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

Step A: (4-Bromo-2-fluoro-3-methoxyphenyl)boronic acid .

A THF solution (9.8 mL) of 2,2,6,6-tetramethylpiperidine TMP (0.98 mL, 5.76 mmol) was cooled to -78 °C under _N2 . To this solution was then slowly added n-BuLi (2.21 N in hexane, 2.45 mL, 5.41 mmol) over several minutes. The mixture was then warmed to 0 °C for 20-30 min and treated with triisopropyl borate (1.25 mL, 5.41 mmol). After 5 min, 1-bromo-3-fluoro-2-methoxybenzene (1.0 g, 4.9 mmol) was added slowly, and the reaction was stirred at -78 °C. After 1.5 h, the resulting mixture was warmed to room temperature with AcOH (2.8 mL, 49 mmol), poured into water, and extracted with EtOAc. The organic extract was separated, dried over MgSO, filtered and concentrated to dryness to give (5-( ₄ -bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-yl)boronic acid ( 940 mg, 77%), the solid was used without further purification.

Step B :

A mixture of crude (4-bromo-2-fluoro-3-methoxyphenyl)boronic acid (940 mg, 1.69 mmol) and 5-bromopyrazin-2-amine (1.31 g, 7.56 mmol) was washed with EtOH (12.4 mL) and toluene (12.8 mL). The resulting suspension was then treated with aqueous Na ₂ CO ₃ (2.0 N, 9.44 mL, 18.9 mmol). The resulting mixture was then bubbled with nitrogen for 10 min before adding Pd(PPh ₃ ) ₄ (218 mg, 0.189 mmol) and heating at 80° C. for 17 h. The reaction was cooled to room temperature and partitioned between saturated _NH4Cl and EtOAc. The organic layer was dried over _MgSO4 and concentrated to dryness. The residue was suspended in DCM and the resulting solid was isolated by filtration to give the title compound (300 mg, 27%) which was used without further purification. The title compound (560 mg, 50%) was obtained by concentrating the DCM layer and subjecting the residue to FCC to obtain additional product. MS (ESI): mass calculated for _C11H9BrFN3O : 296.99; found m/z: _298.0 [ _M +H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ )δ8.34(dd, J=2.6,1.5,1H),8.00(d,J=1.5,1H),7.54-7.49(m,2H),6.78(s,2H ), 3.90 (d, J = 0.6, 3H).

Example 211

5-(4-cyclopentyl-2-fluoro-3-methoxyphenyl)pyrazin-2-amine

In a microwave vial was added 5-(4-bromo-2-fluoro-3-methoxyphenyl)-pyrazin-2-amine (50 mg, 0.17 mmol), palladium acetate (2.9 mg, 0.013 mmol) and 2- Dicyclohexylphosphine-2',6'-dimethoxy-1,1'-diphenyl (7.7 mg, 0.018 mmol). The vial was evacuated and backfilled with nitrogen. Cyclopentylzinc bromide (0.5M in THF, 0.67mL, 0.34mmol) was then added and the mixture was heated at 70°C for 19 hours. The reaction was cooled to room temperature, and the mixture was subjected to HPLC purification to afford the title compound (7 mg, 15%). MS (ESI): mass calculated for C16H18FN3O: _287.14 ; m/z found: _288.1 [ _M +H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.50-8.46 (m, 1H), 8.09 (d, J = 1.5, 1H), 7.54-7.48 (m, 1H), 7.09 (dd, J = 8.3, 1.1, 1H ),4.65(s,2H),3.94(d,J=1.2,3H),3.42-3.33(m,1H),2.11-1.99(m,2H),1.88-1.78(m,2H),1.77-1.66 (m,2H), 1.59-1.53(m,2H).

Example 212

5-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]pyrazin-2-amine

Using conditions similar to those described in Example 83, cyclopentylzinc bromide (0.5M in THF) was used to prepare the title compound. MS (ESI): mass calculated for _C22H22FN3O : _363.17 ; _m /z found: 364.2 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.50(s,1H),8.10(s,1H),7.58–7.51(m,1H),7.51–7.45(m,2H),7.43–7.32(m,3H) ,7.10(dd,J＝8.3,1.1,1H),5.09(s,2H),4.66(s,2H),3.43–3.31(m,1H),2.00–1.89(m,2H),1.84–1.72( m, 2H), 1.71–1.47 (m, 4H).

Example 213

5-[4-cyclopentyl-2-fluoro-3-(1-methylethoxy)phenyl]pyrazin-2-amine

Step A :

Using a method similar to that described in Example 216, 5-(4-chloro-2-fluoro-3-isopropoxyphenyl) was prepared from 4-chloro-2-fluoro-3-isopropoxyphenylboronic acid Pyrazin-2-amine. MS (ESI): mass calculated for _C13H13ClFN3O : _281.07 ; _m /z found: 282.0 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.32 (d, J=3.6, 2H), 7.60 (m, 1H), 7.31-7.22 (m, 1H), 4.52 (m, 1H), 1.41-1.38 (m, 6H).

Step B :

The title compound was prepared using similar conditions as described in Example 83 using 5-(4-chloro-3-isopropoxyphenyl)pyrazin-2-amine and cyclopentylzinc bromide (0.5M in THF) . MS (ESI): mass calculated for _C18H22FN3O : _315.17 ; _m /z found: 316.1 [M+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.48–8.45(m,1H),8.08(d,J=1.5,1H),7.52–7.46(m,1H),7.10(dd,J=8.3,1.2,1H ),4.64(s,2H),4.48–4.38(m,1H),3.49–3.40(m,1H),2.10–2.01(m,2H),1.88–1.79(m,2H),1.75–1.67(m , 2H), 1.58–1.48 (m, 3H), 1.35 (dd, J=6.1, 0.6, 6H).

Instance 214

2-[3-(Benzyloxy)-4-cyclopentyl-2-fluorophenyl]-5H-pyrrolo[2,3-b]pyrazine

Step A :

2-(3-(Benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrole was prepared from 5-bromo-4,7-diazaindole using the method described in Example 216 And[2,3-b]pyrazine. MS (ESI): mass calculated for _C19H13ClFN3O : _353.07 ; _m /z found: 354.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ9.35(s, 1H), 8.70(d, J=2.9, 1H), 7.72-7.65(m, 2H), 7.58-7.51(m, 2H), 7.44-7.30( m, 4H), 6.82 (dd, J = 3.7, 1.9, 1H), 5.20 (s, 2H).

Step B :

Using similar conditions as described in Example 83 with 2-(3-(benzyloxy)-4-chloro-2-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine and cyclopenta Zinc bromide (0.5 M in THF) was used to prepare the title compound. MS (ESI): mass calculated for _C24H22FN3O : _387.1747 ; m/z found: 388.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ9.26(s,1H),8.73(d,J=2.8,1H),7.69–7.61(m,2H),7.50(dd,J=8.1,6.5,2H), 7.43–7.32(m,3H),7.16(dd,J=8.3,1.1,1H),6.82(dd,J=3.7,1.9,1H),5.12(s,2H),3.46–3.33(m,1H) ,2.04–1.91(m,2H),1.87–1.75(m,2H),1.73–1.49(m,4H).

instance 215

5-[3-(Benzyloxy)-4-tert-butylphenyl]pyrazin-2-amine

Step A: 2-(Benzyloxy)-4-bromo-1-(tert-butyl)benzene .

5-Bromo-2-tert-butylphenol (1.08g, 4.71mmol), benzyl bromide (0.69mL, 5.7mmol) and Cs ₂ CO ₃ (2.3g, 7.1mmol) were added to 23.6mL of acetonitrile and heated at room temperature Stirring was continued for 64 hours. The reaction mixture was filtered and concentrated to dryness. Purification by FCC afforded the title compound (1.39 g, 92%).

Step B: 2-(3-(Benzyloxy)-4-(tert-butyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborol alkane

2-(Benzyloxy)-4-bromo-1-(tert-butyl)benzene (495mg, 1.55mmol) and 4,4,4',4',5,5,5',5'-octa Methyl-2,2'-bis(1,3,2-dioxaborolane) (482mg, 1.86mmol) dissolved in 1,4-bis Alkanes (10.3 mL) and treated with EtOAc (461 mg, 4.65 mmol). The solution was bubbled with _N2 and tris((E,E)-dibenzylideneacetone)dipalladium (42 mg, 0.047 mmol) and tricyclohexylphosphine (30 mg, 0.11 mmol) were added. The mixture was heated at 100°C for 4 hours. The reaction mixture was filtered through anhydrous NaSO ₄ and a pad of celite, then subjected to FCC to afford the title compound (138 mg, 24%).

Step C :

2-Amino-5-bromopyrazine (65mg, 0.38mmol) and 2-(3-(benzyloxy)-4-(tert-butyl)phenyl)-4,4,5,5-tetramethyl Ethyl-1,3,2-dioxaborolane (138 mg, 0.38 mmol) was partially dissolved in DME (2.5 mL) and treated with 2.0 M aqueous K ₂ CO ₃ (0.83 mL). The solution was bubbled and treated with Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (30 mg, 0.038 mmol). The mixture was stirred at room temperature for 64 hours. The mixture was dried, filtered through a pad of celite, then subjected to FCC and then HPLC to afford the title compound (4 mg, 2%). MS (ESI): mass calculated for C21H23N3O: _333.18 ; m/z found: _334.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.30 (d, J = 1.4, 1H), 8.18 (d, J = 1.4, 1H), 7.56–7.48 (m, 3H), 7.45–7.32 (m, 6H), 5.21(s,2H), 1.42(s,10H).

Instance 216

5-[3-(Benzyloxy)-4-chloro-2-fluorophenyl]pyrazin-2-amine

2-Amino-5-bromopyrazine (100 mg, 0.57 mmol) and 3-benzyloxy-4-chloro-2-fluorophenylboronic acid (193 mg, 0.57 mmol) were partially dissolved in DME (2.5 mL), and treated with _{2.0 M} aqueous K2CO3 (0.83 mL). The solution was bubbled and treated with Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (47 mg, 0.057 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was dried, filtered through a pad of celite, and then subjected to FCC to afford the title compound (146 mg, 77%). MS (ESI): mass calculated for _C17H13ClFN3O : _329.07 ; _m /z found: 330.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.47 (dd, J = 2.4, 1.6, 1H), 8.06 (d, J = 1.5, 1H), 7.61–7.50 (m, 3H), 7.43–7.31 (m, 3H ), 7.24 (dd, J=8.9, 1.9, 1H), 5.16 (s, 2H), 4.78 (s, 2H).

Instance 217

5-[3-(Benzyloxy)-4-cyclobutylphenyl]pyrazin-2-amine

Step A :

Using a procedure similar to that described in Example 216, 5-(3-benzyloxy)-4-chlorophenyl)pyrazine was prepared from (3-(benzyloxy)-4-chlorophenyl)-boronic acid -2-amine. MS (ESI): mass calculated for _C17H14ClN3O : _311.08 ; _m /z found: 312.1 [M+H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.38(d, J=1.4,1H), 8.03(d, J=1.5,1H), 7.59(d, J=1.9,1H), 7.55-7.48(m,2H ), 7.47-7.36 (m, 4H), 7.33 (t, J=7.4, 1H), 5.24 (s, 2H), 4.69 (s, 2H).

Step B :

Using conditions similar to those described in Example 83, the title compound was prepared from 5-(3-(benzyloxy)-4-chlorophenyl)pyrazin-2-amine. MS (ESI): mass calculated for C21H21N3O: _331.17 ; m/z found: _332.4 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.42 (d, J = 1.5, 1H), 8.06 (d, J = 1.5, 1H), 7.50–7.45 (m, 3H), 7.45–7.37 (m, 3H), 7.36–7.28(m,2H),5.15(s,2H),4.60(s,2H),3.88–3.78(m,1H),2.41–2.30(m,2H),2.23–2.10(m,2H), 2.09–1.95(m,1H),1.88–1.78(m,1H).

Example 218

3-Amino-6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared in a manner similar to that described in Example 198 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 3-amino-6-bromopyrazine-2-carbonitrile . MS (ESI): mass calculated for _C16H15FN4O2 : _298.12 ; m/z found: 299.1 [M ₊ H] ₊ ^{. 1} HNMR (500MHz, CD ₃ OD) δ8.62-8.61 (m, 1H), 7.54-7.46 (m, 1H), 7.21-7.15 (m, 1H), 3.89-3.88 (m, 3H), 3.86-3.79 (m,1H), 2.41-2.32(m,2H), 2.24-2.04(m,3H), 1.94-1.85(m,1H).

Example 219

6-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)pyridazin-3-amine

The title compound was prepared in a manner similar to that described in Example 198 using (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid and 6-chloropyridazin-3-amine. MS (ESI): mass calculated for _C15H16FN3O : _273.13 ; _m /z found: 274.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ7.73-7.62 (m, 2H), 7.17-7.14 (m, 1H), 6.84-6.78 (m, 1H), 3.92-3.87 (m, 3H), 3.86-3.77 ( m, 1H), 2.42-2.32(m, 2H), 2.23-1.98(m, 3H), 1.93-1.83(m, 1H).

instance 220

6-Cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol

The title compound was prepared by reaction of Intermediate I in a manner similar to that described in Example 185. MS (ESI): mass calculated for _C17H15FN2O : _282.12 ; m/z found: _283.1 [M+H] ⁺ . ¹ H NMR (500MHz, CD ₃ OD) δ8.90-8.83 (m, 1H), 8.63-8.56 (m, 1H), 7.82-7.75 (m, 1H), 7.18-7.12 (m, 1H), 7.08-7.01 (m,1H),6.98-6.93(m,1H),3.91-3.76(m,1H),2.45-2.34(m,2H),2.25-2.14(m,2H),2.11-2.02(m,1H) ,1.95-1.85(m,1H).

Example 221

6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenol

Prepared by reaction of 3-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-7H-pyrrolo[2,3-c]pyridazine in a manner similar to that described in Example 185 title compound. MS (ESI): mass calculated for _C16H14FN3O : _283.11 ; _m /z found: 284.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.69-8.65 (m, 1H), 8.57-8.51 (m, 1H), 7.31-7.27 (m, 1H), 7.21-7.16 (m, 1H), 7.10-7.05 (m,1H), 3.95-3.82(m,1H), 2.46-2.38(m,2H), 2.26-2.07(m,3H), 1.95-1.86(m,1H).

Example 222

3-Amino-6-(4-cyclobutyl-2-fluoro-3-hydroxyphenyl)pyrazine-2-carbonitrile

The title compound was prepared by reaction of 3-amino-6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)-pyrazine-2-carbonitrile in a manner similar to that described in Example 185 . MS (ESI): mass calculated for _C15H13FN4O : _284.11 ; m/z found: 285.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.63-8.58(m,1H),7.27-7.20(m,1H),7.11-7.05(m,1H),3.89-3.74(m,1H),2.42-2.31 (m,2H), 2.24-1.99(m,3H), 1.92-1.81(m,1H).

Example 223

3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol

In a manner similar to that described in Example 185, the title compound was prepared by reaction of 6-(4-cyclobutyl-2-fluoro-3-methoxyphenyl)pyridazin-3-amine. MS (ESI): mass calculated for _C14H14FN3O : _259.11 ; _m /z found: 260.1 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.15-8.08 (m, 1H), 7.57-7.50 (m, 1H), 7.22-7.16 (m, 1H), 7.15-7.10 (m, 1H), 3.89-3.76 (m,1H), 2.42-2.33(m,2H), 2.22-2.00(m,3H), 1.92-1.82(m,1H).

Example 224

5,5'-((pyrimidine-2,4-diylbis(oxyl))bis(4-cyclobutyl-2-fluoro-3,1-phenylene))bis(pyrazin-2-amine )

In a manner similar to that described in Example 69, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-4-(methylsulfanyl) Pyrimidine to prepare the title compound. MS (ESI): mass calculated for _C32H28F2N8O2 : _594.23 ; m/z found: _595.3 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, CDCl ₃ ) δ8.50(d, J=5.7,1H), 8.36(d, J=4.4,2H), 7.95(d, J=8.4,2H), 7.61-7.52(m,2H ),7.06-6.99(m,2H),6.81(d,J=5.6,1H),3.61-3.41(m,2H),2.20-1.89(m,10H),1.78(d,J=12.3,2H) .

Example 225

7-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4 ] Zinc

In a manner similar to that described in Example 69, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (oxin-7-yl)-2-fluorophenol and 2-chloropyrimidine. MS (ESI): mass calculated for C ₂₁ H ₁₉ FN ₄ O ₂ : 378.15; m/z found: 379.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.63–8.58(m,2H),7.75–7.71(m,1H),7.66–7.62(m,1H),7.46–7.39(m,1H),7.34–7.28 (m,1H),7.28–7.23(m,1H),4.39–4.33(m,2H),3.73–3.59(m,3H),2.24–2.08(m,4H),2.04–1.93(m,1H) ,1.87–1.76(m,1H).

Example 226

2-(6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] Azin-7-yl)-2-fluorophenoxy)pyrimidin-4-amine

In a manner similar to that described in Example 69, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (oxin-7-yl)-2-fluorophenol and 2-chloro-4-aminopyrimidine. MS (ESI): mass calculated for _C21H20FN5O2 : _393.16 ; m/z found: 394.3 [ _{M +} H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.05–8.00(m,1H),7.76–7.72(m,1H),7.64–7.61(m,1H),7.51–7.45(m,1H),7.36–7.31 (m,1H),6.50–6.45(m,1H),4.39–4.33(m,2H),3.74–3.64(m,3H),2.33–2.23(m,2H),2.23–2.14(m,2H) ,2.11–2.01(m,1H),1.91–1.83(m,1H).

Example 227

7-(4-cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-3,4-dihydro-2H-pyrido[3,2 -b][1,4] Zinc

In a manner similar to that described in Example 69, 6-cyclobutyl-3-(3,4-dihydro-2H-pyrido[3,2-b][1,4] The title compound was prepared from (oxin-7-yl)-2-fluorophenol and 4-chloro-6-methoxypyrimidine. MS (ESI): mass calculated for _C22H21FN4O3 : _408.16 ; _m /z found: 409.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.35–8.30(m,1H),7.75–7.71(m,1H),7.66–7.61(m,1H),7.46–7.39(m,1H),7.34–7.27 (m,1H),6.44–6.39(m,1H),4.40–4.31(m,2H),4.05–3.97(m,3H),3.74–3.67(m,2H),3.67–3.54(m,1H) ,2.28–2.09(m,4H),2.06–1.93(m,1H),1.87–1.78(m,1H).

Example 228

5-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-1H-pyrrolo[2,3-I]pyridine

In a manner similar to that described in Example 69, 6-cyclobutyl-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenol and 4-chloro-6- Methoxypyrimidine to prepare the title compound. MS (ESI): mass calculated for _C22H19FN4O2 : _390.15 ; m/z found: 391.1 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, CD ₃ OD) δ8.51–8.44(m,2H),8.38–8.33(m,1H),7.61–7.56(m,1H),7.54–7.47(m,1H),7.38–7.31 (m,1H),6.77–6.71(m,1H),6.45–6.39(m,1H),4.03–3.98(m,3H),3.70–3.59(m,1H),2.28–2.13(m,4H) ,2.08–1.96(m,1H),1.89–1.79(m,1H).

Example 229

2-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)-5H-pyrrolo[2,3-b]pyrazine

In a manner similar to that described in Example 69, 6-cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol and 4-chloro-6 -Methoxypyrimidine Preparation of the title compound. MS (ESI): mass calculated for C ₂₁ H ₁₈ FN ₅ O ₂ : 391.14; m/z found: 392.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.61–8.57(m,1H),8.38–8.34(m,1H),7.87–7.84(m,1H),7.83–7.77(m,1H),7.40–7.35 (m,1H),6.74–6.69(m,1H),6.43–6.40(m,1H),4.03–3.98(m,3H),3.71–3.60(m,1H),2.26–2.15(m,4H) ,2.08–1.97(m,1H),1.89–1.81(m,1H).

instance 230

2-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)-5H-pyrrolo[2,3-b]pyrazine

Prepared in a manner similar to that described in Example 69 using 6-cyclobutyl-2-fluoro-3-(5H-pyrrolo[2,3-b]pyrazin-2-yl)phenol and 2-chloropyrimidine title compound. MS (ESI): mass calculated for C20H16FN5O: _361.13 ; m/z found: _362.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.65–8.61(m,2H),8.60–8.56(m,1H),7.86–7.83(m,1H),7.82–7.76(m,1H),7.39–7.35 (m,1H),7.28–7.23(m,1H),6.74–6.69(m,1H),3.75–3.64(m,1H),2.26–2.15(m,4H),2.06–1.95(m,1H) ,1.88–1.78(m,1H).

Example 231

6-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyridazin-3-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol and 2-chloropyrimidine. MS (ESI): mass calculated for _C18H16FN5O : _337.13 ; m/z found: _338.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.64–8.59(m,2H),8.16–8.10(m,1H),7.76–7.70(m,1H),7.58–7.53(m,1H),7.39–7.34 (m,1H),7.29–7.24(m,1H),3.74–3.62(m,1H),2.26–2.09(m,4H),2.06–1.94(m,1H),1.87–1.77(m,1H) .

Example 232

6-(4-Cyclobutyl-2-fluoro-3-((6-methoxypyrimidin-4-yl)oxy)phenyl)pyridazin-3-amine

The title compound was prepared in a manner similar to that described in Example 69 using 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidine . MS (ESI): mass calculated for _C19H18FN5O2 : _367.14 ; m/z found: _368.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.29–8.26(m,1H),8.15–8.10(m,1H),7.76–7.70(m,1H),7.57–7.53(m,1H),7.39–7.35 (m,1H),5.84–5.81(m,1H),3.74–3.61(m,1H),3.53–3.47(m,3H),2.35–2.24(m,2H),2.23–2.14(m,2H) ,2.10–1.99(m,1H),1.90–1.81(m,1H).

Example 233

6-(3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidin-4-ol

The title compound was prepared in a manner similar to that described in Example 69 using 3-(6-aminopyridazin-3-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-methoxypyrimidine . MS (ESI): mass calculated for _C18H16FN5O2 : _353.13 ; m/z found: _354.1 [M ₊ H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.15–8.11(m,1H),8.08–8.05(m,1H),7.76–7.71(m,1H),7.57–7.52(m,1H),7.41–7.35 (m,1H),5.81–5.76(m,1H),3.74–3.63(m,1H),2.34–2.24(m,2H),2.24–2.14(m,2H),2.10–2.01(m,1H) ,1.91–1.82(m,1H).

Instance 234

4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidine-2-carbonitrile

The title compound was prepared in a manner similar to that described in Example 96 using 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloropyrimidine-2-carbonitrile. ¹ HNMR (400MHz, CD ₃ OD) δ8.99 (s, 1H), 8.76-8.72 (m, 1H), 8.53 (d, J = 6.1, 1H), 8.00 (d, J = 6.1, 1H), 7.38 -7.30(m,1H),7.12(d,J＝8.1,1H),3.89-3.77(m,1H),2.42-2.32(m,2H),2.24-2.14(m,2H),2.11-2.00( m,1H), 1.92-1.83(m,1H).

Example 235

6-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N,2-trimethylpyrimidin-4-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 6-chloro-N,N,2-trimethyl Pyrimidin-4-amine Preparation of the title compound. MS (ESI): mass calculated for _C21H23FN6O : _394.19 ; m/z found: _395.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.30-8.25 (m, 1H), 8.11 (d, J = 1.5, 1H), 7.89-7.82 (m, 1H), 7.38 (d, J = 8.0, 1H) ,5.74(s,1H),3.71-3.61(m,1H),3.17(s,6H),2.53(s,3H),2.34-2.18(m,4H),2.13-2.00(m,1H),1.94 -1.83(m,1H).

Instance 236

4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N,6-trimethylpyrimidin-2-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-N,N,6-trimethyl Pyrimidin-2-amine Preparation of the title compound. MS (ESI): mass calculated for _C21H23FN6O : _394.19 ; m/z found: _395.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.25–8.22 (m, 1H), 8.12 (d, J = 1.5, 1H), 7.82 (t, J = 7.9, 1H), 7.33 (d, J = 8.3, 1H),6.65(d,J=0.7,1H),3.67–3.57(m,1H),3.19–2.95(m,5H),2.56(d,J=0.6,3H),2.30–2.15(m,4H ), 2.08–1.99(m,1H), 1.91–1.81(m,1H).

Instance 237

6-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N,N-dimethylpyrimidin-4-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 6-chloro-N,N-dimethylpyrimidine- 4-Amine Preparation of the title compound. MS (ESI): mass calculated for _C20H21FN6O : _380.18 ; m/z found: 381.1 [ _M +H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.26 (d, J = 1.4, 1H), 8.23–8.18 (m, 2H), 7.86–7.79 (m, 1H), 7.32 (d, J = 8.1, 1H) ,6.11(d,J=0.6,1H),3.70–3.59(m,1H),3.14(d,J=10.6,6H),2.29–2.14(m,4H),2.08–1.95(m,1H), 1.90–1.80(m,1H).

Instance 238

5-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole- 4-Ethyl carboxylate

In a manner similar to that described in Example 96, 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 5-chloro-1-methyl-3-(tri Fluoromethyl)-1H-pyrazole-4-carboxylic acid ethyl ester to prepare the title compound. MS (ESI): mass calculated for _C22H21F4N5O3 : _479.16 ; _m /z found: _480.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.19(d, J=1.4,1H), 8.11(d, J=1.6,1H), 7.71-7.64(m,1H), 7.32(d, J=8.3, 1H), 3.99-3.86(m, 6H), 2.42-2.23(m, 4H), 2.16-2.05(m, 1H), 1.96-1.87(m, 1H), 0.98(t, J=7.1, 3H).

Example 239

5-(4-Cyclobutyl-2-fluoro-3-((5-(methylsulfanyl)pyridin-2-yl)oxy)phenyl)pyrazin-2-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 2-chloro-5-(methylsulfanyl) Pyridine to prepare the title compound. MS (ESI): mass calculated for _C20H19FN4O3S : _414.12 ; m/z found: _415.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.61-8.59(m,1H),8.37-8.33(m,1H),8.25(d,J＝1.4,1H),8.19(s,1H),7.85-7.78 (m,1H),7.33-7.29(m,2H),3.68-3.56(m,1H),3.18(s,3H),2.23-2.12(m,4H),2.04-1.93(m,1H),1.86 -1.77(m,1H).

instance 240

4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6-(tert-butyl)pyrimidin-2-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-(tert-butyl)-6-chloropyrimidine- 2-Amine Preparation of the title compound. MS (ESI): mass calculated for _C22H25FN6O : _{408.21 ;} m/z found: 409.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.27-8.23 (m, 1H), 8.10 (d, J = 1.5, 1H), 7.79 (t, J = 7.9, 1H), 7.31 (d, J = 8.2, 1H),6.76(s,1H),3.69-3.59(m,1H),2.30-2.15(m,4H),2.09-1.98(m,1H),1.91-1.82(m,1H),1.44(s, 9H).

Example 241

5-(3-((4-(1,5-dioxa-9-azaspiro[5.5]undec-9-yl)pyrimidin-2-yl)oxy)-4-cyclobutyl- 2-fluorophenyl)pyrazin-2-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 9-(2-chloropyrimidin-4-yl)- 1,5-Dioxa-9-azaspiro[5.5]undecane Preparation of the title compound. MS (ESI): mass calculated for _C26H29FN6O3 : _{492.23 ; m} /z found: 493.2 [M+H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.25(s, 1H), 8.16(s, 1H), 8.11(d, J=7.4, 1H), 7.86(t, J=7.9, 1H), 7.36(d ,J=8.3,1H),6.89-6.86(m,1H),3.87(t,J=5.5,4H),3.74-3.57(m,5H),2.35-2.16(m,4H),2.12-2.02( m, 1H), 1.96-1.63 (m, 7H).

instance 242

4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-6-isobutylpyrimidin-2-amine

In a manner similar to that described in Example 96, with 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol and 4-chloro-6-isobutylpyrimidine-2- Amines to prepare the title compound. MS (ESI): mass calculated for _C22H25FN6O : _{408.21 ;} m/z found: 409.1 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.26(s, 1H), 8.07(d, J=1.4, 1H), 7.77(t, J=7.9, 1H), 7.28(d, J=8.3, 1H) ,6.66(s,1H),3.68-3.57(m,1H),2.65(d,J=7.4,2H),2.30-2.23(m,2H),2.21-2.15(m,2H),2.13-2.08( m, 1H), 2.07-2.01 (m, 1H), 1.91-1.83 (m, 1H), 1.05 (d, J=6.6, 6H).

Intermediate I

5-(4-Cyclobutyl-2-fluoro-3-methoxyphenyl)-1H-pyrrolo[2,3-b]pyridine

Add a stir bar, 5-bromo-7-azaindole (59 mg, 0.30 mmol), (4-cyclobutyl-2-fluoro-3-methoxyphenyl)boronic acid (74 mg, 0.33 mmol), 14.7 mg Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (15 mg, 0.18 mmol), and K ₂ CO ₃ (129 mg, 0.93 mmol). The vial was purged with nitrogen and filled with sparged toluene (0.50 mL), sparged water (0.50 mL) and sparged DMF (0.30 mL). The vial was heated at 80 °C for 24 h, then cooled to room temperature, the reaction mixture was diluted with DCM, the mixture was dried _over MgSO, filtered through a pad of celite and concentrated to dryness. The dark residue was subjected to FCC to afford the title compound (67 mg, 76%) as a white solid. MS (ESI): mass calculated for _C18H17N2FO : _296.13 , m/z found: 297.1 [M ₊ H] ⁺ . ¹ HNMR (600MHz, CDCl ₃ )δ9.88(s,1H),8.52–8.46(m,1H),8.13–8.09(m,1H),7.42–7.37(dd,J＝3.5,2.3,1H), 7.21–7.16(m,1H),7.16–7.11(m,1H),6.59–6.54(dd,J=3.5,1.9,1H),3.93(s,3H),3.89–3.79(m,1H),2.43 –2.34 (m, 2H), 2.24 – 2.14 (m, 2H), 2.13 – 2.02 (m, 1H), 1.93 – 1.85 (m, 1H).

Example 243

N-(2-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-ethyl)-methane-sulfonamide

N-(2-chloroethyl)methanesulfonamide (146mg, 0.93mmol), 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (200mg, 0.77mmol) , Cs ₂ CO ₃ (376 mg, 1.16 mmol) and DMF (6 mL) was stirred at room temperature for 16 h, then treated with water (10 mL). The mixture was extracted with EtOAc (3 x 20 mL). The combined organic phases were dried, concentrated to dryness, and the residue was purified by FCC to afford the title compound (165 mg, 56%). MS (CI): mass calculated for _C21H21FN4O3S : _380.13 ; _m /z found: 381.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.43(s, 1H), 8.08(s, 1H), 7.55(m, 1H), 7.15(d, J=8.2Hz, 1H), 5.44–5.26(m, 1H ),4.78(s,2H),4.10(t,J＝4.9Hz,2H),3.84–3.69(m,1H),3.60–3.49(m,2H),3.05(s,3H),2.42–2.27( m,2H), 2.22–2.01(m,3H), 1.94–1.80(m,1H).

instance 244

5-(4-Cyclobutyl-2-fluoro-3-(2-morpholineethoxy)phenyl)pyrazin-2-amine

Using conditions similar to those described in Example 243, the title compound was prepared from 4-(2-bromoethyl)morpholine. MS (CI): mass calculated for _C20H25FN4O2 : _372.20 ; m/z found: 373.1 [ _{M +} H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.51–8.42 (m, 1H), 8.09 (d, J = 1.4, 1H), 7.54 (m, 1H), 7.15 (d, J = 8.2, 1H), 4.74 ( s, 2H), 4.18(t, J=5.3, 2H), 3.84(dd, J=18.0, 6.6, 5H), 2.89(s, 2H), 2.70(s, 4H), 2.39–2.32(m, 2H ), 2.20–2.12 (m, 2H), 2.08–2.01 (m, 1H), 1.88 (d, J=10.4, 1H).

Instance 245

Ethyl 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoate

Using conditions similar to those described in Example 243, the title compound was prepared using ethyl 4-bromobutyrate. MS (CI): mass calculated for C20H24FN3O3: _373.18 ; _m /z found: 374.1 _{[ M} +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.52–8.38 (m, 1H), 8.08 (d, J = 1.6, 1H), 7.53 (m, 1H), 7.14 (d, J = 8.2, 1H), 4.65 ( s,2H),4.17(q,J=7.2,2H),4.04(t,J=6.2,2H),3.86–3.75(m,1H),2.59(t,J=7.4,2H),2.39–2.30 (m, 2H), 2.20–2.03 (m, 5H), 1.87 (ddd, J = 11.3, 10.3, 8.7, 1H), 1.28 (t, J = 7.1, 3H).

Instance 246

tert-butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)azetidine-1-carboxylate

Using conditions similar to those described in Example 243, the title compound was prepared from tert-butyl 3-(((methylsulfanyl)oxy)methyl)azetidine-1-carboxylate. MS (CI): mass calculated for _C23H29FN4O3 : _428.22 ; _m /z found: 429.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.45(s, 1H), 8.09(d, J=1.2, 1H), 7.54(m, 1H), 7.15(d, J=8.2, 1H), 4.70(s, 2H), 4.16(d, J＝6.5, 2H), 4.09(t, J＝8.5, 2H), 3.90–3.83(m, 2H), 3.82–3.73(m, 1H), 3.04–2.92(m, 1H ), 2.40–2.28(m,2H), 2.21–2.01(m,3H), 1.92–1.83(m,1H), 1.45(s,9H).

Instance 247

tert-Butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate

Using conditions similar to those described in Example 243, the title compound was prepared from tert-butyl 3-(((methylsulfanyl)oxy)methyl)pyrrolidine-1-carboxylate. MS (CI): mass calculated for C ₂₄ H ₃₁ FN ₄ O ₃ : 442.24; m/z found: 465.2 [M+Na] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.48–8.43 (m, 1H), 8.09 (d, J = 1.5, 1H), 7.53 (m, 1H), 7.14 (d, J = 8.3, 1H), 4.65 ( s,2H),4.04–3.91(m,2H),3.86–3.75(m,1H),3.69–3.34(m,3H),3.29-3.25(m,1H),2.71-2.63(m,1H), 2.38-2.31 (m, 2H), 2.19-2.03 (m, 4H), 1.92-1.76 (m, 2H), 1.48 (s, 9H).

Instance 248

tert-Butyl 2-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)pyrrolidine-1-carboxylate

Using conditions similar to those described in Example 243, the title compound was prepared from tert-butyl 2-(((methylsulfanyl)oxy)methyl)pyrrolidine-1-carboxylate. MS (CI): mass calculated for _C24H31FN4O3 : _442.24 ; _m /z found: 443.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.46(s,1H),8.08(s,1H),7.55(s,1H),7.13(s,1H),4.64(s,2H),4.09(s,2H ),3.85-3.77(m,2H),3.42(s,2H),2.39–2.25(m,3H),2.18-1.98(m,5H),1.92–1.81(m,2H),1.44(s,9H ).

Example 249

tert-Butyl 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl)piperidine-1-carboxylate

Using conditions similar to those described in Example 243, the title compound was prepared using tert-butyl 2-(bromomethyl)piperidine-1-carboxylate. MS (CI): mass calculated for _C25H33FN4O3 : _456.25 ; _m /z found: 457.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.45(m,1H),8.09(m,1H),7.52(m,1H),7.14(d,J=8.2,1H),4.63(s,2H),4.30 –4.18(m,1H),4.04–3.93(m,1H),3.91–3.85(m,2H),3.83–3.75(m,1H),2.88–2.72(m,2H),2.41–2.30(m, 2H), 2.24–1.96(m,5H), 1.95–1.80(m,2H), 1.76–1.67(m,1H), 1.57–1.50(m,1H), 1.48(s,9H).

Instance 250

2-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)ethanol

The title compound was prepared using conditions similar to those described in Example 243 from 2-(2-bromoethoxy)tetrahydro-2H-pyran. The initial alkylated product was treated with 0.2M HCl in methanol and the resulting mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the residue was subjected to FCC to obtain the title compound. MS (CI): mass calculated for _C16H18FN3O2 : _303.14 ; _m /z found: 304.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.28(d, J=1.6,1H),7.99(d,J=1.4,1H),7.50(t,J=7.9,1H),7.20(d,J =8.2,1H),6.64(s,2H),4.86(t,J=5.5,1H),3.98(t,J=5.0,2H),3.85(dd,J=17.8,8.8,1H),3.70( dd,J=10.4,5.2,2H),2.30(ddd,J=13.8,8.3,5.8,2H),2.14–2.05(m,2H),2.02–1.95(m,1H),1.82(dd,J= 18.6, 9.3, 1H).

Example 251

4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoic acid

Dissolve ethyl 4-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)butanoate (300 mg, 0.8 mmol) in THF (6 mL), and A solution of LiOH.H2O (101 mg, 2.41 mmol) and water (2 mL) was added. The reaction was stirred overnight, then the mixture was acidified to pH=7 by addition of 1M HCl. The mixture was concentrated to dryness and subjected to FCC to afford the title compound (135 mg.45%). MS (CI): mass calculated for C18H20FN3O3: _345.15 ; _m /z found: 346.1 _{[ M} +H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ12.22(s,1H),8.38–8.29(m,1H),8.05(d,J=1.6,1H),7.56(m,1H),7.26(d, J=8.2,1H),6.70(s,2H),4.02(t,J=6.4,2H),3.87–3.77(m,1H),2.50(t,J=7.3,2H),2.40–2.30(m ,2H), 2.20–1.99(m,5H), 1.92–1.83(m,1H).

Example 252

5-(4-Cyclobutyl-2-fluoro-3-((tetrahydrofuran-2-yl)methoxy)phenyl)pyrazin-2-amine

The title compound was prepared using similar conditions described in Example 243 from 2-(bromomethyl)tetrahydro-[2H]-pyran at 60°C. MS (CI): mass calculated for _C19H22FN3O2 : _343.17 ; _m /z found: 344.1 [M ₊ H] ⁺ . ¹ H NMR (400MHz, CDCl ₃ ) δ8.56–8.37 (m, 1H), 8.08 (d, J = 1.5, 1H), 7.53 (dd, J = 10.2, 5.4, 1H), 7.15 (d, J = 8.3 ,1H),4.62(s,2H),4.34–4.21(m,1H),4.08–4.03(m,1H),4.00–3.81(m,4H),2.41–2.32(m,2H),2.17–1.82 (m,8H).

Example 253

rac 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(isobutylamino)propan-2-ol

Step A: 5-(4-Cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine .

The title compound was prepared from (rac)-epichlorohydrin using conditions similar to those described in Example 243, heating at 60°C. ¹ HNMR (400MHz, CDCl ₃ ) δ8.57–8.40 (m, 1H), 8.08 (d, J = 1.5, 1H), 7.54 (dd, J = 14.2, 6.6, 1H), 7.15 (d, J = 8.2 ,1H),4.64(s,2H),4.28(dd,J=11.2,3.2,1H),3.98(dd,J=11.2,6.1,1H),3.92–3.81(m,1H),3.38(td, J=6.4,3.2,1H),2.92–2.86(m,1H),2.72(dd,J=5.0,2.6,1H),2.43–2.34(m,2H),2.20–2.01(m,3H),1.93 –1.83(m,1H).

Step B: 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-(isobutylamino) -propan-2-ol .

5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyrazin-2-amine (150mg, 0.48mmol), isobutylamine (105mg , 1.43 mmol) and MeOH (5 mL) was heated to 60° C. in a sealed tube for 5 h, then the solvent was removed. The residue was subjected to FCC to afford the title compound (125 mg, 67%). MS (CI): mass calculated for _C21H29FN4O2 : _388.23 ; m/z found: 389.2 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, CDCl ₃ ) δ8.48–8.39 (m, 1H), 8.08 (d, J = 1.4, 1H), 7.54 (m, 1H), 7.14 (d, J = 8.2, 1H), 4.72 ( s,2H),4.45–4.37(m,1H),4.09–3.99(m,2H),3.86–3.73(m,1H),3.29–3.21(m,1H),3.16–3.07(m,1H), 2.86–2.69 (m, 2H), 2.41–2.30 (m, 2H), 2.19–2.01 (m, 4H), 1.90–1.81 (m, 1H), 1.05 (d, J=6.7, 6H).

Instance 254

rac 3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)propane-1,2-diol

The title compound was obtained by opening the epoxide 5-(4-cyclobutyl-2-fluoro-3-(oxiran-2-ylmethoxy)phenyl)pyridine in water using the conditions in Step B of Example 253. A by-product found with oxazin-2-amine. MS (CI): mass calculated for _C17H20FN3O3 : _333.15 ; _m /z found: 334.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.28(s, 1H), 7.99(d, J=1.4, 1H), 7.50(m, 1H), 7.20(d, J=8.2, 1H), 6.64( s,2H),4.93(d,J=5.1,1H),4.64(t,J=5.6,1H),4.02-3.97(m,1H),3.92-3.83(m,2H),3.82-3.77(m , 1H), 3.46 (t, J=5.6, 2H), 2.35-2.27 (m, 2H), 2.14-1.95 (m, 3H), 1.86-1.78 (m, 1H).

Instance 255

rac 1-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-3-morpholin-2-ol

Using conditions similar to those described in Example 253, the title compound was prepared in Step B from morpholine. MS (CI): mass calculated for _C21H27FN4O3 : _402.21 ; _m /z found: 403.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.48–8.44(m,1H),8.09(d,J=1.5,1H),7.58–7.53(m,1H),7.16(d,J=8.2,1H), 4.67(s,2H),4.18(s,1H),4.03(d,J=4.9,2H),3.88–3.83(m,1H),3.79(s,4H),2.76(s,2H),2.68( s,2H),2.60(s,2H),2.40–2.33(m,2H),2.17(dt,J＝9.3,5.4,2H),2.09–2.00(m,1H),1.93–1.84(m,1H ).

Instance 256

Racemic 4-(3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)thiomorpholine 1,1 - Dioxide

Using conditions similar to those described in Example 253, the title compound was prepared in Step B from thiomorpholine 1,1-dioxide. MS (CI): mass calculated for _C21H27FN4O4S : _450.17 ; m/z found: _451.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.26(s,1H),7.98(m,1H),7.48(m,1H),7.18(d,J=8.2,1H),6.62(s,2H) ,4.94(d,J=4.4,1H),3.96-3.79(m,4H),3.12-3.03(m,4H),3.02-2.95(m,4H),2.68(dd,J=13.2,4.3,1H ), 2.61-2.52(m,1H), 2.31-2.23(m,2H), 2.13-1.92(m,3H), 1.83-1.73(m,1H).

Instance 257

5-(4-Cyclobutyl-2-fluoro-3-(pyridazin-4-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 160, using DMSO as solvent, heating by microwave irradiation at 80 °C for 2 hours, and substituting Intermediate B and 4-bromo-pyridazine hydrobromide. MS (ESI): mass calculated for _C18H16FN5O : _337.13 ; m/z found: _338.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ9.12-9.05 (m, 1H), 9.01-8.95 (m, 1H), 8.47-8.41 (m, 1H), 8.11 (d, J = 1.5Hz, 1H), 7.91 -7.82(m,1H),7.35-7.28(m,1H),6.83-6.75(m,1H),4.84(s,2H),3.63-3.49(m,1H),2.28-2.06(m,4H) ,2.08-1.90(m,1H),1.90-1.79(m,1H).

Instance 258

3-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrazin-2-amine

Using conditions similar to those described in Example 160, using DMSO as solvent, heating by microwave irradiation at 140° C. for 2 hours, and substituting Intermediate B and 2-amino-3-chloropyrazine, the title compound was prepared. MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.1 [M+H] ⁺ . ¹ HNMR(400MHz,DMSO-d ₆ )δ8.29-8.23(m,3H),8.01(d,J=1.5Hz,3H),7.76-7.68(m,3H),7.61(d,J=3.0Hz ,3H),7.28(d,J=8.3Hz,3H),7.14(d,J=3.0Hz,3H),6.70(s,11H),3.62-3.49(m,3H),2.17-2.00(m, 12H), 1.98-1.83 (m, 3H), 1.81-1.67 (m, 3H).

Example 259

5-(4-Cyclobutyl-2-fluoro-3-(pyrazin-2-yloxy)phenyl)pyrazin-2-amine

Using conditions similar to those described in Example 160, using DMSO as solvent, heating by microwave irradiation at 80° C. for 2 hours, and substituting Intermediate B and 2-fluoropyrazine, the title compound was prepared. MS (ESI): mass calculated for _C18H16FN5O : _337.13 ; m/z found: _337.9 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.53(d, J=1.3Hz, 1H), 8.49-8.42(m, 1H), 8.27(d, J=2.7Hz, 1H), 8.12-8.03(m, 2H ),7.85-7.76(m,1H),7.23(s,1H),4.70(s,2H),3.68-3.56(m,1H),2.26-2.08(m,4H),2.03-1.89(m,1H ), 1.87-1.76(m,1H).

instance 260

5-(4-Cyclobutyl-2-fluoro-3-(pyrimidin-4-yloxy)phenyl)pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 101, using pyridine as solvent, heating at 80°C for 18 hours, and substituting 4-chloropyrimidine hydrochloride. MS (ESI): mass calculated for _C18H16FN5O : _337.13 ; m/z found: _338.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.76(s, 1H), 8.62(d, J=5.8Hz, 1H), 8.47-8.45(m, 1H), 8.09(d, J=1.4Hz, 1H), 7.82(m,1H),7.24(d,J=8.3Hz,1H),7.02(dd,J=5.8,1.0Hz,1H),4.67(s,2H),3.59(m,1H),2.25-2.08 (m, 4H), 2.03-1.89 (m, 1H), 1.86-1.76 (m, 1H).

Example 261

4-(3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-N-isobutylpyrimidin-2-amine trifluoroacetate

Step A: 5-{3-[(2-Chloropyrimidin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

Example 137 was prepared from 2,4-dichloropyrimidine using conditions similar to those described in Example 101, using DMSO as solvent and heating by microwave irradiation at 120°C for 1 hour.

Step B :

The crude material from step A was treated with 10 equivalents of isobutylamine and heated at 140 °C for 1 h by microwave irradiation. The resulting mixture was subjected to FCC followed by reverse phase HPLC to afford 6 mg (6%) of the title compound. MS (ESI): mass calculated for _C22H25FN6O : _{408.21 ;} m/z found: 409.2 [M+H] ⁺ . ¹ HNMR(400MHz, CDCl ₃ )δ10.38–10.29(m,1H),8.38(d,J=1.1Hz,1H),8.22(s,1H),7.99(d,J=6.8Hz,1H), 7.96–7.88(m,1H),7.31–7.23(m,1H),6.46(d,J＝6.8Hz,1H),3.63–3.49(m,1H),2.94–2.84(m,2H),2.31– 1.96 (m, 4H), 1.93–1.81 (m, 1H), 1.68–1.54 (m, 1H), 0.66 (d, J=6.7Hz, 6H).

Instance 262

2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-benzo Methyl azole-5-carboxylate

Using similar conditions as described in Example 69, with 2-(chloromethyl)benzo[d] Azole-5-carboxylic acid methyl ester to prepare the title compound. MS (ESI): mass calculated for _C24H21FN4O4 : _448.15 ; m/z found: 449.1 [ _{M +} H] ⁺ .

Instance 263

Methyl 3-({[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetyl}amino)-4-hydroxybenzoate

The title compound was a by-product in the preparation of Example 262. MS (ESI): mass calculated for _C24H23FN4O5 : _466.17 ; m/z found: _467.1 [ _M +H] ⁺ .

Instance 264

5-[4-Cyclobutyl-2-fluoro-3-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 69, the title compound was prepared from 4-bromomethyltetrahydropyran. MS (ESI): mass calculated for C20H24FN3O2: _357.19 ; _m /z found: 358.1 [ _{M +} H] ⁺ .

Instance 265

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-(methylsulfanyl)benzonitrile

Using conditions similar to those described in Example 69, the title compound was prepared from 4-fluoro-3-(methylsulfanyl)benzonitrile. MS (ESI): mass calculated for _C22H19FN4O3 : _438.12 ; _m /z found: 439.1 [M ₊ H] ⁺ .

Instance 266

5-{3-[2,4-Bis(trifluoromethyl)phenoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

Using conditions similar to those described in Example 69, the title compound was prepared from 2,4-bis-(trifluoromethyl)fluorobenzene. MS (ESI): mass calculated for _C22H16F7N3O : _471.12 ; _m /z found: _472.1 [M+H] ⁺ .

Instance 267

5-{4-cyclobutyl-3-[3-(dimethylamino)propoxy]-2-fluorophenyl}pyrazin-2-amine

Using conditions similar to those described in Example 243, the title compound was prepared from 3-chloro-N,N-dimethylpropan-1-amine hydrochloride. MS (ESI): mass calculated for _C19H25FN4O : _344.20 ; m/z found: 345.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.45(s, 1H), 8.09(d, J=1.3, 1H), 7.53(m, 1H), 7.14(d, J=8.2, 1H), 4.73(s, 2H), 4.06(t, J=6.0, 2H), 3.88-3.71(m, 1H), 2.90-2.75(m, 2H), 2.47(s, 6H), 2.36-2.32(m, 2H), 2.20- 2.02(m,5H),1.89-1.84(m,1H).

Instance 268

5-{4-cyclobutyl-3-[2-(dimethylamino)ethoxy]-2-fluorophenyl}pyrazin-2-amine

Using conditions similar to those described in Example 243, the title compound was prepared from 2-chloro-N,N-dimethylethylamine hydrochloride. MS (ESI): mass calculated for _C18H23FN4O : _330.19 ; m/z found: 331.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.52-8.39 (m, 1H), 8.09 (d, J = 1.5, 1H), 7.56 (m, 1H), 7.16 (d, J = 8.4, 1H), 4.64 ( s,2H),4.25(s,2H),3.84-3.79(m,1H),3.06(s,2H),2.64(s,6H),2.41-2.31(m,2H),2.23-2.02(m, 3H), 1.93-1.83 (m, 1H).

Instance 269

4-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-N,6-dimethylpyrimidin-2-amine

Using conditions similar to those described in Example 69, the title compound was prepared from 4-chloro-N,6-dimethylpyrimidin-2-amine. MS (ESI): mass calculated for _C20H21FN6O : _380.18 ; m/z found: 381.2 [ _M +H] ⁺ .

Instance 270

2-[6-Cyclobutyl-2-fluoro-3-(7H-pyrrolo[2,3-c]pyridazin-3-yl)phenoxy]pyrimidin-4-amine

Using similar conditions as described in Example 69, with 4-amino-2-chloropyrimidine and 6-cyclobutyl-2-fluoro-3-{7-[(4-methylphenyl)-sulfanyl]- 7H-Pyrrolo[2,3-c]pyridazin-3-yl}phenol The title compound was prepared. MS (ESI): mass calculated for C20H17FN6O: _376.14 ; m/z found: _376.9 [ _M +H] ⁺ .

Example 271

5-{4-cyclobutyl-3-[(6,7-difluoroquinoxalin-2-yl)oxy]-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared from 2-chloro-6,7-difluoroquinoxaline by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): Mass calculated for _C22H16F3N5O : _423.13 ; m/z found: _424.0 [ _M +H]+. ¹ HNMR (500MHz, CD ₃ OD) δ8.86(s, 1H), 8.31–8.21(m, 1H), 8.06(dd, J=1.5, 0.7, 1H), 7.94(dd, J=10.7, 8.3, 1H),7.82–7.75(m,1H),7.59(dd,J=11.1,8.1,1H),7.33(d,J=8.3,1H),3.78–3.54(m,1H),2.19(t,J =8.9,4H), 2.01–1.93(m,1H), 1.85–1.77(m,1H).

Instance 272

2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]quinazolin-4-amine

The title compound was prepared from 2-chloroquinazolin-4-amine by heating under microwave irradiation at 120°C for 1 hour using conditions similar to those described in Example 101. MS (ESI): mass calculated for _C22H19FN6O : 402.16 _; m/z found: _403.2 [M+H]+. ¹ HNMR (500MHz, CD ₃ OD) δ8.29(d, J=2.1,1H), 8.10–7.97(m,2H), 7.69(dd, J=13.1,6.9,2H), 7.55(d, J= 8.5,1H),7.41–7.33(m,1H),7.26(d,J=8.3,1H),3.71(t,J=9.0,1H),2.28–2.08(m,4H),2.02–1.92(m , 1H), 1.81 (d, J=9.6, 1H).

Instance 273

2-Amino-5-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyrimidine-4-carbonitrile

Using conditions similar to those described in Example 69, the title compound was prepared from 2-amino-5-bromopyrimidine-4-carbonitrile. MS (ESI): mass calculated for _C19H16FN7O : _377.14 ; m/z found: _377.9 [M+H] ⁺ .

Instance 274

2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3-benzo Methyl azole-5-carboxylate

Using similar conditions as described in Example 69, with 2-(chloromethyl)benzo[d] Azole-5-carboxylic acid methyl ester to prepare the title compound. MS (ESI): mass calculated for _C24H21FN4O4 : _448.15 ; m/z found: 449.1 [ _{M +} H] ⁺ .

Instance 275

Methyl 3-({[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetyl}amino)-4-hydroxybenzoate

The title compound was a by-product in the preparation of Example 274. MS (ESI): mass calculated for _C24H23FN4O5 : _466.17 ; m/z found: _467.1 [ _M +H] ⁺ .

Instance 276

[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]acetonitrile

Using conditions similar to those described in Example 69, the title compound was prepared using chloroacetonitrile. MS (ESI): mass calculated for _C16H15FN4O : _298.12 ; m/z found: 299.1 [M ₊ H] ⁺ .

Instance 277

5-[4-Cyclobutyl-2-fluoro-3-(pyridazin-3-yloxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 69, the title compound was prepared from 3-chloropyridazine. MS (ESI): mass calculated for _C18H16FN5O : _337.13 ; m/z found: _338.1 [M+H] ⁺ .

Instance 278

5-[4-Cyclopropyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 101, 2-bromopyrimidine and 3-(5-aminopyrazin-2-yl)-6-cyclopropyl-2- Fluorophenol to prepare the title compound. MS (ESI): mass calculated for _C17H14FN5O : _323.12 ; m/z found: _324.1 [M+H]+. ¹ H NMR (400MHz, CD ₃ OD) δ8.62 (d, J = 4.8, 2H), 8.25 (dd, J = 2.3, 1.5, 1H), 8.04 (d, J = 1.5, 1H), 7.69–7.61 ( m,1H), 7.29–7.21(m,1H), 6.95–6.86(m,1H), 2.07–1.87(m,1H), 0.95–0.82(m,2H), 0.74–0.65(m,2H).

Instance 279

2-[3-(5-Aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenoxy]pyrimidin-4-amine

Using conditions similar to those described in Example 101, heating with 2-chloropyrimidin-4-amine and 3-(5-aminopyrazin-2-yl)-6-cyclopropane by microwave irradiation at 120 °C for 1 hour -2-fluorophenol to prepare the title compound. MS (ESI): mass calculated for _C17H15FN6O : _{338.13 ;} m/z found: 339.1 [M+H]+. ¹ HNMR (400MHz, CD ₃ OD) δ8.31–8.22(m,1H),8.03(d,J=1.5,1H),7.88(d,J=5.9,1H),7.65–7.57(m,1H) , 6.85 (d, J = 8.5, 1H), 6.25 (d, J = 5.9, 1H), 2.02–1.91 (m, 1H), 0.91 (m, 2H), 0.75–0.68 (m, 2H).

Instance 280

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-imidazol-2-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 2-(chloromethyl)-1-methyl-1H-imidazole hydrochloride. MS (ESI): mass calculated for _C19H20FN5O : _353.17 ; m/z found: 354.2 [ _M +H] ⁺ .

Example 281

2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3- Methyl azole-4-carboxylate trifluoroacetate

Using similar conditions as described in Example 69, with 2-(chloromethyl) Azole-4-carboxylic acid methyl ester to prepare the title compound. MS (ESI): mass calculated for _C20H19FN4O4 : _398.14 ; m/z found: 399.1 [ _{M +} H] ⁺ .

Instance 282

2-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}-1,3- Azole-4-carboxylic acid trifluoroacetate

The title compound was obtained as a by-product in the preparation of Example 284. MS (ESI): mass calculated for _C19H17FN4O4 : _384.12 ; m/z found: 385.1 [M ₊ H] ₊ ^.

Example 283

5-[3-(1,3-Benzothiazol-2-ylmethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 2-(chloromethyl)benzo[d]thiazole. MS (ESI): mass calculated for _C22H19FN4OS : _406.13 ; m/z found: 407.1 [M ₊ H] ⁺ .

Instance 284

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-imidazol-4-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 4-(chloromethyl)-1-methyl-1H-imidazole hydrochloride. MS (ESI): mass calculated for _C19H20FN5O : _353.17 ; m/z found: _354.1 [M+H] ⁺ .

Instance 285

5-{4-Cyclobutyl-2-fluoro-3-[(1-methyl-1H-imidazol-5-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 5-(chloromethyl)-1-methyl-1H-imidazole hydrochloride. MS (ESI): mass calculated for _C19H20FN5O : _353.17 ; m/z found: _354.1 [M+H] ⁺ .

Instance 286

2-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}pyridine-3-carbonitrile trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 2-(chloromethyl)nicotinonitrile. MS (ESI): mass calculated for _C19H20FN5O : _375.15 ; m/z found: _354.1 [M+H] ⁺ .

Instance 287

5-{4-Cyclobutyl-2-fluoro-3-[(2-methyl-1,3-thiazol-4-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 4-(chloromethyl)-2-methylthiazole. MS (ESI): mass calculated for _C19H19FN4OS : _370.13 ; m/z found: 371.0 [M ₊ H] ⁺ .

Instance 288

5-[4-Cyclobutyl-2-fluoro-3-(pyridazin-3-ylmethoxy)phenyl]pyrazin-2-amine trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 3-(chloromethyl)pyridazine. MS (ESI): mass calculated for _C19H18FN5O : _351.15 ; m/z found: _352.1 [M+H] ⁺ .

Instance 289

5-{3-[(5-Chloropyridin-2-yl)methoxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 5-chloro-2-(chloromethyl)pyridine. MS (ESI): mass calculated for _C20H18FClN4O : _384.12 ; m/z found: 385.0 [ _M +H] ⁺ .

Instance 290

5-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}pyridine-2-carbonitrile trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 5-(chloromethyl)cyanopyridine. MS (ESI): mass calculated for _C21H18FN5O : _375.15 ; m/z found: _376.1 [M+H] ⁺ .

Example 291

5-{4-cyclobutyl-2-fluoro-3-[(5-methyliso Azol-3-yl)methoxy]phenyl}pyrazin-2-amine trifluoroacetate

Using similar conditions as described in Example 69, with 3-(chloromethyl)-5-methyliso azole to prepare the title compound. MS (ESI): mass calculated for _C19H19FN4O2 : _354.15 ; m/z found: 355.1 [M ₊ H] ₊ ^.

Example 292

6-{[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}pyridine-2-carbonitrile trifluoroacetate

Using conditions similar to those described in Example 69, the title compound was prepared from 6-(chloromethyl)cyanopyridine. MS (ESI): mass calculated for _C21H18FN5O : _375.15 ; m/z found: _376.0 [M+H] ⁺ .

Example 293

2-{2-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}-1H-isoindole-1,3(2H)- diketone

Using conditions similar to those described in Example 69, the title compound was prepared from 2-(2-bromoethyl)isoindoline-1,3-dione. MS (ESI): mass calculated for _C24H21FN4O3 : _432.16 ; _m /z found: 433.0 [ _M +H] ⁺ .

Instance 294

5-[3-(2-Aminoethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine

To 2-{2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}-1H-isoindole-1,3( A 200 mL round bottom flask of 2H)-diketone (550 mg, 1.27 mmol) was charged with a stir bar and EtOH (26 mL). The mixture was then sparged thoroughly ( _N2 sparged through), and hydrazine monohydrate (1.00 mL, 21 mmol) was added to the flask. The flask was then heated at 77°C for 22 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, washed with NaOH (1 N x 3), dried over MgSO4, filtered and concentrated to dryness to give the desired product (365 mg, 95%). MS (ESI): mass calculated for _C16H19FN4O : _302.15 ; m/z found: 303.1 [M ₊ H] ⁺ .

Example 295

5-{4-Cyclobutyl-2-fluoro-3-[2-(pyrazin-2-ylamino)ethoxy]phenyl}pyrazin-2-amine trifluoroacetate

Add a stir bar (spin-vane), 5-[3-(2-aminoethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine (47mg, 0.16 mmol), 2-fluoropyrazine (35 mg, 0.35 mmol) and Cs ₂ CO ₃ (115 mg, 0.35 mmol). The flask was purged thoroughly with nitrogen, DMSO (1.0 mL) was added, heated at 100 °C for 14.5 hours, then cooled to room temperature, the solid was filtered off and the filtrate was subjected to HPLC purification to give the title compound (26 mg, 34%). MS (ESI): mass calculated for _C20H21FN6O : _380.18 ; m/z found: 381.1 [ _M +H] ⁺ .

Instance 296

N-{2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}pyrimidin-2-amine trifluoroacetate

Using conditions similar to those described in Example 295, the title compound was prepared from 2-chloropyrimidine. MS (ESI): mass calculated for _C20H21FN6O : _380.18 ; m/z found: 381.1 [ _M +H] ⁺ .

Instance 297

N-{2-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]ethyl}pyrimidin-4-amine

Using conditions similar to those described in Example 295, the title compound was prepared from 4-chloropyrimidine. MS (ESI): mass calculated for _C20H21FN6O : _380.18 ; m/z found: 381.1 [ _M +H] ⁺ .

Instance 298

5-[4-Cyclobutyl-2-fluoro-3-(piperidin-4-ylmethoxy)phenyl]pyrazin-2-amine hydrochloride

Using similar conditions as described in Step A of Example 68, 4-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)piper tert-Butyl pyridine-1-carboxylate to prepare the title compound. MS (ESI): mass calculated for C20H25FN4O: _356.20 ; m/z found: _357.1 [ _M +H] ⁺ .

Example 299

rac 5-[4-cyclobutyl-2-fluoro-3-(piperidin-3-ylmethoxy)phenyl]pyrazin-2-amine

Using similar conditions as described in Step A of Example 68, racemic 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl ) tert-butyl piperidine-1-carboxylate to prepare the title compound. MS (ESI): mass calculated for _C20H25FN4O : _356.20 ; m/z found: 357.2 [ _M +H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ )δ8.60(s,1H),8.43(s,1H),8.08(s,1H),7.53(m,1H),7.13(d,J＝8.2,1H),4.69 (s,2H),3.96-3.83(m,2H),3.80-3.68(m,1H),3.65-3.57(m,1H),3.52-3.35(m,1H),2.93-2.76(m,2H) ,2.55-2.38(m,1H),2.38-2.27(m,2H),2.19-1.83(m,7H),1.63-1.44(m,1H).

Instance 300

rac 5-[4-cyclobutyl-2-fluoro-3-(pyrrolidin-3-ylmethoxy)phenyl]pyrazin-2-amine

Using similar conditions as described in Step A of Example 68, racemic 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluoro-phenoxy)methanol base) tert-butyl pyrrolidine-1-carboxylate to prepare the title compound. MS (ESI): mass calculated for _C19H23FN4O : _342.19 ; m/z found: 343.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ9.90(s, 1H), 8.43(d, J=1.7, 1H), 8.08(d, J=1.1, 1H), 7.53(m, 1H), 7.14(d, J＝8.2,1H),4.73(s,2H),4.12-3.97(m,2H),3.78-3.64(m,2H),3.55-3.39(m,2H),3.38-3.28(m,1H), 2.99-2.81 (m, 1H), 2.39-2.26 (m, 3H), 2.19-2.01 (m, 4H), 1.92-1.83 (m, 1H).

instance 301

5-[3-(azetidin-3-ylmethoxy)-4-cyclobutyl-2-fluorophenyl]pyrazin-2-amine

Using similar conditions as described in Step A of Example 68, 3-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)-methyl)acridine Butidine-1-carboxylic acid tert-butyl ester to prepare the title compound. MS (ESI): mass calculated for _C18H21FN4O : _328.17 ; m/z found: 329.5 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.35(s,1H),8.27(s,1H),7.98(s,1H),7.52(m,1H),7.20(d,J＝8.2,1H) ,6.65(s,2H),4.10(d,J=5.7,2H),4.06-3.96(m,2H),3.87-3.77(m,2H),3.77-3.69(m,1H),3.17-3.09( m, 1H), 2.33-2.19 (m, 2H), 2.15-1.92 (m, 3H), 1.87-1.74 (m, 1H).

instance 302

rac 5-[4-cyclobutyl-2-fluoro-3-(pyrrolidin-2-ylmethoxy)phenyl]pyrazin-2-amine

Using similar conditions as described in Step A of Example 68, racemic 2-((3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)methyl ) tert-butyl pyrrolidine-1-carboxylate to prepare the title compound. MS (ESI): mass calculated for _C19H23FN4O : _342.19 ; m/z found: 343.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.26(d, J=1.5,1H),7.97(d,J=1.4,1H),7.49(m,1H),7.19(d,J=8.2,1H ),6.63(s,2H),3.98-3.88(m,2H),3.85-3.76(m,1H),3.59-3.52(m,1H),3.01-2.91(m,2H),2.32-2.24(m ,2H), 2.17-1.89(m,5H), 1.84-1.70(m,3H), 1.61-1.51(m,1H).

instance 303

rac 51-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-piperidin-1-ylpropan-2-ol

Using conditions similar to those described in Example 51, piperidine was used to prepare the title compound. MS (ESI): mass calculated for _C22H29FN4O2 : _400.23 ; m/z found: 401.2 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, CD ₃ OD) δ8.28-8.23 (m, 1H), 8.03 (d, J = 1.5, 1H), 7.50 (m, 1H), 7.22 (d, J = 8.2, 1H), 4.58 (s,2H),4.43-4.34(m,1H),4.04-3.94(m,2H),3.95-3.85(m,1H),3.34(dd,J=8.4,4.9,2H),3.23(d, J=13.2,2H), 2.37(m,2H), 2.25-2.12(m,2H), 2.08(m,1H), 1.93-1.79(m,5H), 1.68(s,2H).

instance 304

Racemic 1-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-(methylamino)propan-2-ol

Using conditions similar to those described in Example 51, the title compound was prepared from methylamine. MS (ESI): mass calculated for _C18H23FN4O2 : 346.18; m/z found: _347.4 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, CD ₃ OD) δ8.32-8.23 (m, 1H), 8.11-8.00 (m, 1H), 7.51 (m, 1H), 7.23 (d, J = 8.2, 1H), 4.29-4.21 (m,1H),4.08-3.98(m,2H),3.95-3.86(m,1H),3.39-3.35(m,1H),3.25-3.20(m,1H),2.79(s,3H),2.44 -2.34(m,2H),2.23-2.06(m,3H),1.96-1.86(m,1H).

instance 305

Racemic 1-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-[(1-methylethyl)amino]propan-2 -alcohol

Using conditions similar to those described in Example 51, the title compound was prepared from isopropylamine. MS (ESI): mass calculated for _C20H27FN4O2 : 374.21; m/z found: 375.5 [ _{M +} H] ₊ ^{. 1} HNMR (400MHz, DMSO-d ₆ ) δ8.31-8.21 (m, 1H), 7.97 (d, J = 1.4, 1H), 7.50 (m, 1H), 7.19 (d, J = 8.2, 1H), 6.64(s,2H),5.73(s,1H),4.19-4.07(m,1H),3.99-3.89(m,2H),3.88-3.76(m,1H),3.27-3.22(m,1H), 3.15-3.07(m,1H),2.98-2.88(m,1H),2.34-2.23(m,2H),2.14-1.90(m,3H),1.86-1.73(m,1H),1.24-1.14(m ,6H).

Instance 306

Racemic 1-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-pyrrolidin-1-ylpropan-2-ol

Using conditions similar to those described in Example 51, the title compound was prepared with pyrrolidine. MS (ESI): mass calculated for _C21H27FN4O2 : _386.21 ; m/z found: 387.2 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, CDCl ₃ ) δ8.54-8.36 (m, 1H), 8.09 (d, J = 1.4, 1H), 7.55 (m, 1H), 7.15 (d, J = 8.2, 1H), 4.71 ( s,2H),4.23-4.12(m,1H),4.02(d,J=5.1,2H),3.94-3.78(m,1H),3.20(s,1H),2.99-2.92(m,1H), 2.91-2.83 (m, 2H), 2.78-2.68 (m, 3H), 2.42-2.31 (m, 2H), 2.21-2.01 (m, 3H), 1.93-1.81 (m, 5H).

Instance 307

Racemic 1-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-(dimethylamino)propan-2-ol

Using conditions similar to those described in Example 51, the title compound was prepared from dimethylamine. MS (ESI): mass calculated for _C19H25FN4O2 : _360.20 ; m/z found: 361.2 [M ₊ H] ₊ ^{. 1} HNMR (400MHz, DMSO-d ₆ ) δ8.26(s, 1H), 7.97(d, J=1.4, 1H), 7.49(m, 1H), 7.19(d, J=8.2, 1H), 6.64( s,2H),5.41(s,1H),4.08(s,1H),3.91-3.79(m,3H),2.88-2.82(m,1H),2.81-2.72(m,1H),2.51(s, 6H), 2.32-2.23(m, 2H), 2.12-1.92(m, 3H), 1.84-1.73(m, 1H).

Instance 308

Diastereomers of 1-{3-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}pyrrolidin-3-ol mixture

Using conditions similar to those described in Example 51, the title compound was prepared from racemic 3-hydroxypyrrolidine. MS (ESI): mass calculated for _C21H27FN4O3 : _402.21 ; _m /z found: 403.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.28-8.23 (m, 1H), 7.97 (d, J = 1.4, 1H), 7.48 (m, 1H), 7.19 (d, J = 8.4, 1H), 6.63(s,2H),5.46-5.14(m,1H),4.96(d,J＝14.5,1H),4.28-4.21(m,1H),4.06-3.98(m,1H),3.93-3.79(m ,3H), 3.07-2.64(m,6H), 2.33-2.24(m,2H), 2.13-1.94(m,4H), 1.86-1.75(m,1H), 1.70-1.57(m,1H).

Instance 309

Racemic 1-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-3-piperazin-1-ylpropan-2-ol

Using conditions similar to those described in Example 51, piperazine was used to prepare the title compound. MS (ESI): mass calculated for _C21H28FN5O2 : _401.22 ; m/z found: _402.2 [M ₊ H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.28(s, 1H), 8.00(d, J=1.4, 1H), 7.50(m, 1H), 7.21(d, J=8.3, 1H), 6.66( s,2H),4.95(s,1H),4.01-3.82(m,4H),2.97(t,J=4.9,4H),2.63(s,3H),2.58-2.53(m,1H),2.52- 2.49 (m, 2H), 2.47-2.41 (m, 1H), 2.35-2.26 (m, 2H), 2.16-1.94 (m, 3H), 1.88-1.78 (m, 1H).

instance 310

Racemic 1-{3-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}pyrimidine-2(1H)- ketone

Using conditions similar to those described in Example 51, the title compound was prepared from 2-pyrimidinone. MS (ESI): mass calculated for _C21H22FN5O3 : _411.17 ; _m /z found: _412.1 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.55(dd, J=4.2,2.8,1H),8.32-8.26(m,1H),8.10(dd,J=6.5,2.8,1H),8.00(d ,J=1.5,1H),7.52(m,1H),7.22(d,J=8.3,1H),6.64(s,2H),6.43(dd,J=6.4,4.2,1H),5.48(d, J=5.8,1H),4.33(dd,J=13.0,3.3,1H),4.19(t,J=7.1,1H),3.96(d,J=5.2,2H),3.85(dd,J=17.7, 8.7,1H),3.71(dd,J=13.0,9.0,1H),2.32(m,2H),2.10(m,2H),2.00(dd,J=17.9,7.9,1H),1.87-1.78(m ,1H).

Example 311

rac 1-{3-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}-1,3-dihydro -2H-benzimidazol-2-one

Using conditions similar to those described in Example 51, the title compound was prepared from 1H-benzo[d]imidazol-2(3H)-one. MS (ESI): mass calculated for _C24H24FN5O3 : _449.19 ; _m /z found: 450.0 [ _M +H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ10.83(s, 1H), 8.29-8.24(m, 1H), 7.99(d, J=1.5, 1H), 7.50(m, 1H), 7.23-7.13( m,2H),7.06-6.93(m,3H),6.63(s,2H),5.36(d,J=4.9,1H),4.18(s,1H),4.00-3.91(m,3H),3.89- 3.78 (m, 2H), 2.32-2.20 (m, 2H), 2.14-2.01 (m, 2H), 1.99-1.89 (m, 1H), 1.79 (dd, J = 18.7, 9.1, 1H).

instance 312

Racemic 1-{3-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl}imidazolidin-2-one

Using conditions similar to those described in Example 51, the title compound was prepared from imidazolidin-2-one. MS (ESI): mass calculated for _C20H24FN5O3 : _401.19 ; _m /z found: 402.1 [ _M +H] ⁺ . ¹ HNMR (400MHz,DMSO-d ₆ )δ8.28(s,1H),7.99(s,1H),7.50(m,1H),7.21(d,J=8.2,1H),6.64(s,2H) ,6.31(s,1H),5.20(d,J=4.7,1H),3.94(s,1H),3.87(s,3H),3.25(dd,J=19.6,11.7,5H),3.09(dd, J=13.8,7.0,1H),2.30(d,J=7.9,2H),2.15-2.05(m,2H),2.00(d,J=9.9,1H),1.82(d,J=9.1,1H) .

Instance 313

2'-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5,5'-dipyrimidin-2-amine

Step A: 5-(3-((5-bromopyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine .

Add 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol (100 mg, 0.386 mmol), 5-bromo-2-chloropyrimidine ( 74mg, 0.39mmol), cesium carbonate (188mg, 0.580) and DMSO (2mL). The vial was sealed and heated in the microwave at 120°C for 30 minutes. The mixture was cooled to room temperature, then passed through a syringe filter, and the filtrate was subjected to HPLC purification to afford the title compound. ¹ HNMR (500MHz, 2mL) δ8.69 (d, J = 1.5, 2H), 8.24 (s, 1H), 8.10 (s, 1H), 7.79–7.69 (m, 1H), 7.27 (d, J = 8.3 ,1H), 3.72–3.58(m,1H), 2.23–2.10(m,3H), 2.02–1.94(m,1H), 1.89–1.75(m,1H).

Step B: 2'-[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]-5,5'-dipyrimidin-2-amine .

5-(3-((5-bromopyrimidin-2-yl)oxy)-4-cyclobutyl-2-fluorophenyl)pyrazin-2-amine (60mg, 0.14mmol) and 5-(4 , 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (32 mg, 0.14 mmol) was added to a sealable microwave vial equipped with a stir bar middle. join 1,4-di Alkane (0.58mL) and Na ₂ CO ₃ (2M, 0.14mL), the mixture was bubbled with Ar for 10min, then Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (5mg, 0.007mmol) was added and the reaction mixture was Heat at 80°C for 15 hours. The reaction was then cooled to room temperature, diluted with water (5 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated to dryness. The crude product was purified by HPLC to afford the title compound. MS (ESI): mass calculated for _C22H19FN8O : _430.17 ; m/z found: _431.1 [M+H]+. ¹ HNMR (500MHz, CD ₃ OD) δ8.83(s,2H),8.67(s,2H),8.23(s,1H),8.16(s,1H),7.82–7.74(m,1H),7.30( d,J=8.3,1H), 3.68(p,J=8.9,1H), 2.31–2.08(m,4H), 2.07–1.92(m,1H), 1.92–1.76(m,1H).

Intermediate J

3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol

Step A: tert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane .

To a stirred solution of 2-fluoro-6-methylphenol (176 mg, 1.40 mmol) in DCM (6.3 mL) cooled to 0 °C was added imidazole (142 mg, 2.09 mmol) followed by tert-butyldimethyl chloride Silane (231 mg, 1.54 mmol). The flask was warmed to room temperature and stirred for 2 hours, then the reaction mixture was poured into water (50 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to dryness to give the title compound which was used without further purification. ¹ HNMR (500MHz, CDCl ₃ ) δ6.91–6.85(m,2H),6.80–6.73(m,1H),2.24(t,J＝0.7,3H),1.02(s,9H),0.20(d, J=2.5,6H).

Step B: (3-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)boronic acid .

To a 25 mL flask was added a stir bar, 2.1 mL of anhydrous THF and 2,2,6,6-tetramethylpiperidine (0.22 mL, 1.0 mmol). The flask was cooled to -78°C and then treated with n-BuLi (0.48 mL, 1.9 mmol, 2.5M in hexane) for 2 minutes. The resulting mixture was stirred for 5 min, then warmed to 0 °C. After 30 min, the mixture was recooled to -78 °C and treated with B(O-iPr) ₃ (0.26 mL, 1.1 mmol) for 4 min. After 15 min, a solution consisting of tert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane (247 mg, 1.03 mmol) in anhydrous THF (2.1 mL) was added over 6 min, and stirred at - Stirring was continued at 78°C for 1 hour. The mixture was then warmed to room temperature, treated with HOAc (0.5 mL), then poured into water (100 mL) and stirred for 5 min. The aqueous mixture was then extracted with EtOAc (3 x 100 mL), the combined extracts _were dried over _Na2SO4 , filtered, and concentrated to dryness to afford the title compound, which was used directly in the next synthetic step.

Step C: 5-(3-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)pyrazin-2-amine .

(3-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)boronic acid (292mg, 1.03mmol), 2-amino-5-bromopyrazine (179mg ,1.03mmol), 1,4-di Alkanes (6.1 mL) and _Na2CO3 ( _2.1 mL, 2M) were added to a microwave vial, and the resulting mixture was bubbled with argon for 10 min. Pd(dppf)Cl2 _- DCM was then added to the mixture, the vial was sealed and heated at 80°C for 16 hours. The reaction mixture was then cooled to room temperature, diluted with water (5 mL), extracted with EtOAc (4 x 5 mL). The combined organic extracts were then dried _{over Na2SO4} , filtered and concentrated to dryness to afford the title compound. This compound was used directly in the next synthetic step without purification.

Step D: 3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol .

5-(3-((tert-butyldimethylsilyl)oxy)-2-fluoro-4-methylphenyl)pyrazin-2-amine (342 mg, 1.03 mmol) was dissolved in THF (1.2 mL), then treated with tetrabutylammonium fluoride (1.2 mL, 1 M in THF). The reaction was stirred at room temperature for 1 h, then diluted with water (10 mL) and extracted with EtOAc (10 mL x 4). The combined organic extracts were washed with brine, dried _{over Na2SO4} , filtered and concentrated to dryness. The crude product was purified by FCC to afford the title compound. ¹ HNMR (500MHz, CD ₃ OD) δ8.26(dd, J=2.3,1.5,1H),8.01(d,J=1.5,1H),7.09(m,1H),6.94(m,1H),2.25 (s,3H).

Intermediate K

3-(5-aminopyrazin-2-yl)-6-ethyl-2-fluorophenol

Step A: 2-fluoro-6-vinylphenol .

To a round bottom flask equipped with a stir bar was added methyltriphenylphosphine bromide (5.6 g, 16 mmol) and anhydrous THF (50 mL). The mixture was stirred until homogeneous, then cooled to 0 °C. Then n-BuLi (6.85 mL, 2.5 M in hexane) was added dropwise to the flask. The resulting solution was stirred for 30 minutes, then transferred via cannula to a stirred mixture of 3-fluoro-2-hydroxybenzaldehyde (1 g, 7 mmol) and THF (28 mL) at room temperature under an atmosphere of argon. The resulting mixture was stirred for 3 h, then quenched with saturated _NH4Cl (50 mL), diluted with water and extracted with diethyl ether (3 x 100 mL). The combined ether extracts were dried over magnesium sulfate, filtered through a pad of silica gel and concentrated to dryness to give the title compound which was used without further purification. ¹ HNMR (500MHz, CDCl ₃ )δ7.20(m,1H),7.04-6.92(m,2H),6.80(m,1H),5.81(dd,J=17.8,1.3,1H),5.69(s, 1H), 5.35 (dd, J = 11.2, 1.3, 1H).

Step B: tert-butyl(2-fluoro-6-vinylphenoxy)dimethylsilane .

The title compound was prepared in Step A of Intermediate J using 2-fluoro-6-vinylphenol in a similar manner to tert-butyl(2-fluoro-6-methylphenoxy)dimethylsilane. ¹ HNMR (500MHz, CDCl ₃ ) δ7.26(m, 1H), 7.03(dd, J=17.8, 11.1, 1H), 6.96(m, 1H), 6.89-6.81(m, 1H), 5.68(dd, J = 17.8, 1.3, 1H), 5.34-5.24 (m, 1H), 1.02 (s, 9H), 0.19 (d, J = 2.4, 6H).

Step C: tert-butyl(2-ethyl-6-fluorophenoxy)dimethylsilane .

To a stirred solution of tert-butyl(2-fluoro-6-vinylphenoxy)dimethylsilane (1.18 g, 4.67 mmol) in ethyl acetate (61 mL) was added 497 mg of 10% carbon-supported palladium. The flask was then fitted with a hydrogen balloon and the reaction mixture was stirred rapidly for 4 hours. The hydrogen balloon was removed, and the reaction mixture was bubbled with nitrogen, then passed through a piece of Filter and elute with EtOAc. The filtrate was concentrated to dryness to give the title compound which was used without further purification. ¹ HNMR (500MHz, CDCl ₃ ) δ6.94-6.85(m, 2H), 6.85-6.77(m, 1H), 2.65(q, J=7.6, 2H), 1.19(t, J=7.5, 3H), 1.02 (s, 9H), 0.21 (d, J = 2.7, 6H).

Step D: 3-(5-aminopyrazin-2-yl)-6-ethyl-2-fluorophenol .

In a similar manner to 3-(5-aminopyrazin-2-yl)-2-fluoro-6-methylphenol, in steps BD of intermediate J, tert-butyl (2-ethyl-6- Fluorophenoxy)dimethylsilane to prepare the title compound. ¹ HNMR (500MHz, CD ₃ OD) δ8.26(dd, J=2.3,1.5,1H),8.02(d,J=1.5,1H),7.12(dd,J=8.0,7.3,1H),6.99- 6.93 (m, 1H), 2.68 (q, J=7.5, 2H), 1.21 (t, J=7.5, 3H).

Intermediate L

3-(5-aminopyrazin-2-yl)-6-cyclopropyl-2-fluorophenol

The title compound was prepared in Step B using cyclopropylzinc bromide using conditions analogous to those described in Method 2 for 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol . ¹ HNMR (500MHz, CD ₃ OD) δ8.29–8.24(m,1H),8.02(d,J=1.5,1H),7.16–7.05(m,1H),6.65(dd,J=8.2,1.3, 1H), 2.28–2.11(m,1H), 1.02–0.90(m,2H), 0.72–0.63(m,2H).

Intermediate M

3-(5-aminopyrazin-2-yl)-2-fluoro-6-isopropylphenol

The title compound was prepared in Step B using isopropylzinc bromide using conditions analogous to those described in Method 2 for 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol . MS (ESI): mass calculated for _C13H14FN3O : _247.11 ; _m /z found: 248.1 [M+H]+.

Intermediate N

3-(5-aminopyrazin-2-yl)-2-fluoro-6-propylphenol

The title compound was prepared in Step B using propylzinc bromide using conditions analogous to those described in Method 2 for 3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenol. MS (ESI): mass calculated for _C13H14FN3O : _247.11 ; _m /z found: 248.1 [M+H]+.

Instance 314

5-[2-fluoro-4-methyl-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 101, 2-chloropyrimidine and 3-(5-aminopyrazin-2-yl)-2-fluoro-6-methyl Phenol to prepare the title compound. MS (ESI): mass calculated for _C15H12FN5O : _297.10 ; m/z found: _298.0 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.61 (d, J = 4.8, 2H), 8.22-8.20 (m, 1H), 8.20-8.19 (m, 1H), 7.73-7.68 (m, 1H), 7.27 -7.24 (m, 1H), 7.22 (m, 1H), 2.23 (d, J=0.7, 3H).

instance 315

2-[3-(5-Aminopyrazin-2-yl)-2-fluoro-6-methylphenoxy]pyrimidin-4-amine

Using conditions similar to those described in Example 101, 2-chloropyrimidin-4-amine and 3-(5-aminopyrazin-2-yl)-2-fluoro- 6-Methylphenol to prepare the title compound. MS (ESI): mass calculated for _C15H13FN6O : _{312.11 ;} m/z found: 313.0 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.29-8.25 (m, 1H), 8.04 (d, J = 1.5, 1H), 7.87 (d, J = 5.9, 1H), 7.63-7.53 (m, 1H) , 7.15 (d, J=8.1, 1H), 6.25 (d, J=5.9, 1H), 2.22 (s, 3H).

Instance 316

5-[4-Ethyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 101, 2-chloropyrimidine and 3-(5-aminopyrazin-2-yl)-6-ethyl-2-fluoro Phenol to prepare the title compound. MS (ESI): mass calculated for _C16H14FN5O : _311.12 ; m/z found: _312.3 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ8.61 (d, J = 4.8, 2H), 8.20 (dd, J = 6.7, 1.6, 2H), 7.74 (dd, J = 8.3, 7.5, 1H), 7.29-7.21 ( m, 2H), 2.63 (q, J = 7.6, 2H), 1.17 (t, J = 7.6, 3H).

Instance 317

2-[3-(5-Aminopyrazin-2-yl)-6-ethyl-2-fluorophenoxy]pyrimidin-4-amine

Using conditions similar to those described in Example 101, 2-chloropyrimidin-4-amine and 3-(5-aminopyrazin-2-yl)-6-ethyl -2-Fluorophenol to prepare the title compound. MS (ESI): mass calculated for _C16H15FN6O : _{326.13 ;} m/z found: 327.3 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ8.27 (m, 1H), 8.04 (d, J = 1.5, 1H), 7.87 (d, J = 5.9, 1H), 7.63 (m, 1H), 7.17 (dd, J = 8.1, 1.3, 1H), 6.24 (d, J = 5.9, 1H), 2.62 (q, J = 7.6, 2H), 1.19 (t, J = 7.6, 3H).

Instance 318

5-[2-fluoro-4-(1-methylethyl)-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 101, 2-chloropyrimidine and 3-(5-aminopyrazin-2-yl)-2-fluoro-6-isopropyl phenol to prepare the title compound. MS (ESI): mass calculated for _C17H16FN5O : _325.13 ; m/z found: _326.3 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.62 (d, J = 4.8, 2H), 8.25 (s, 1H), 8.04 (d, J = 1.5, 1H), 7.72 (t, J = 7.9, 1H) , 7.28 (dd, J = 8.4, 1.4, 1H), 7.25 (m, 1H), 3.18-3.10 (m, 1H), 1.22 (d, J = 6.9, 6H).

Instance 319

5-[2-fluoro-4-propyl-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 101, heating with 2-chloropyrimidine and 3-(5-aminopyrazin-2-yl)-2-fluoro-6-propyl by microwave irradiation at 120 °C for 1 hour Phenol to prepare the title compound. MS (ESI): mass calculated for _C17H16FN5O : _325.13 ; m/z found: _326.3 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.61(d, J=4.8, 2H), 8.25(s, 1H), 8.04(d, J=1.5, 1H), 7.71-7.62(m, 1H), 7.27 -7.23(m,1H),7.20(dd,J=8.2,1.4,1H),2.58(t,J=7.6,2H),1.66-1.51(m,2H),0.90(t,J=7.3,3H ).

instance 320

5-(4-cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

Step A: tert-butyl(2-cyclohexyl-6-fluorophenoxy)dimethylsilane .

(2-Bromo-6-fluorophenoxy)(tert-butyl)dimethylsilane (0.832g, 2.73mmol) and bis(tri-tert-butylphosphine)palladium(0) (0.070g, 0.14mmol) and A solution consisting of anhydrous THF (5 mL) was treated with cyclohexylzinc(II) bromide (7.0 mL, 3.5 mmol, 0.5 M in THF). The resulting mixture was heated at 50 °C for 45 minutes, cooled to room temperature, and concentrated to dryness. The resulting residue was subjected to FCC purification to afford the title compound (0.841 g, 89%) which was used without purification.

Step B: (3-((tert-butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)boronic acid .

A solution consisting of 2,2,6,6-tetramethylpiperidine (0.50 mL, 3.0 mmol) and anhydrous THF (2 mL) was cooled to -78 °C and washed with n-butyllithium (1.1 mL, 2.75 mmol, 2.5M hexane solution). After stirring for 5 minutes, the reaction was allowed to warm to room temperature and held for 5 minutes before cooling to -78°C. The reaction was then treated with tert-butyl(2-cyclohexyl-6-fluorophenoxy)dimethylsilane (0.719 g, 2.33 mmol) and triisopropyl borate (0.60 mL, 2.6 mmol) and stirred for 5 minutes . The reaction mixture was warmed to room temperature, quenched with saturated _NH4Cl (2 mL), and extracted with EtOAc (2 x 5 mL). The combined organic extracts were washed with brine (3 x 5 mL), dried over MgSO ₄ , filtered, and concentrated to dryness to give the title compound (0.833 g, 101%) which was used without purification.

Step C: 5-(3-((tert-butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)pyrazin- 2-amine .

(3-((tert-Butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)boronic acid (0.821 g, 2.33 mmol), 5-bromopyrazin-2-amine ( 0.40g, 2.3mmol), K ₂ CO ₃ (0.659g, 4.77mmol), Pd(dppf)Cl ₂ ·CH ₂ Cl ₂ (0.086g, 0.12mmol), deoxygenated toluene (10mL) and deoxygenated deionized water (10mL ) mixture was heated at 80°C for 16 hours. The reaction mixture was then cooled to room temperature, diluted with dichloromethane (25 mL), and washed with brine (2 x 25 mL). The organic layer was dried over _MgSO4 , filtered and concentrated to dryness to give the title compound (0.936 g, 100%) which was used without purification.

Step D: 3-(5-aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenol .

5-(3-((tert-butyldimethylsilyl)oxy)-4-cyclohexyl-2-fluorophenyl)pyrazin-2-amine (936mg, 2.33mmol) and THF (15mL) The resulting solution was treated with tetrabutylammonium fluoride (5 mL, 5 mmol, 1 M in THF). The reaction mixture was stirred for 16 hours at which time it was concentrated to dryness and purified by FCC to afford the title compound (0.403 g, 60%) which was used without purification. MS (ESI): mass calculated for C16H18FN3O: _287.14 ; m/z found: _288.1 [ _M +H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.47-8.45 (m, 1H), 8.09 (d, J=1.5, 1H), 7.32 (m, 1H), 7.06-7.03 (m, 1H), 5.60 (d, J＝6.3,1H),4.65(s,2H),3.00-2.92(m,1H),1.94-1.81(m,4H),1.80-1.74(m,1H),1.52-1.38(m,4H), 1.33-1.25(m,1H).

Step E: 5-(4-cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine .

3-(5-aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenol (0.05g, 0.2mmol), 2-chloropyrimidine (0.025g, 0.22mmol), K ₂ CO ₃ (0.05 g, 0.4 mmol) and a mixture of 18-crown-6 (0.01 g, 0.04 mmol) and DMSO (2 mL) was heated at 120 °C for 1 h by microwave irradiation. After cooling to room temperature, the reaction mixture was filtered and directly purified by HPLC to afford the title compound (42 mg, 65%). MS (ESI): mass calculated for _C20H20FN5O : _365.17 ; m/z found: 366.1 [ _M +H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.63-8.60 (m, 2H), 8.28-8.24 (m, 1H), 8.20-8.18 (m, 1H), 7.80-7.76 (m, 1H), 7.31-7.23 (m,2H), 2.81-2.74(m,1H), 1.83-1.68(m,5H), 1.53-1.43(m,2H), 1.35-1.24(m,3H).

Example 321

5-(4-(cyclohexylmethyl)-2-fluoro-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

In a manner similar to that described in Example 320, the title compound was prepared in Step A using (cyclohexylmethyl)zinc(II) bromide. MS (ESI): mass calculated for _C21H22FN5O : _379.18 ; m/z found: _380.1 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.61 (d, J = 4.8, 2H), 8.26 (d, J = 1.5, 1H), 8.21-8.19 (m, 1H), 7.75-7.71 (m, 1H) ,7.27-7.24(m,1H),7.20-7.15(m,1H),2.49(d,J=7.1,2H),1.68-1.60(m,5H),1.55-1.47(m,1H),1.17- 1.09(m,3H),0.98-0.88(m,2H).

Example 322

5-(2-fluoro-4-isopentyl-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

In a manner similar to that described in Example 320, the title compound was prepared in Step A using isopentylzinc(II) bromide. MS (ESI): mass calculated for _C19H20FN5O : _353.17 ; m/z found: _354.1 [M+H] ⁺ . ¹ H NMR (500MHz, CD ₃ OD) δ8.65-8.59 (m, 2H), 8.28-8.26 (m, 1H), 8.21-8.19 (m, 1H), 7.77-7.73 (m, 1H), 7.29-7.20 (m,2H),2.65-2.57(m,2H),1.56-1.48(m,1H),1.46-1.39(m,2H),0.85(s,3H),0.83(s,3H).

Instance 323

5-(2-fluoro-4-isobutyl-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

In a manner similar to that described in Example 320, the title compound was prepared in Step A using isobutylzinc(II) bromide. MS (ESI): mass calculated for _C18H18FN5O : _339.15 ; m/z found: _340.1 [M+H] ⁺ . ¹ H NMR (500MHz, CD ₃ OD) δ8.61 (d, J = 4.8, 2H), 8.27 (d, J = 1.4, 1H), 8.20 (m, 1H), 7.75 (t, J = 7.8, 1H) , 7.25 (m, 1H), 7.22–7.19 (m, 1H), 2.49 (d, J=7.3, 2H), 1.91–1.84 (m, 1H), 0.88 (d, J=6.6, 6H).

Instance 324

5-(2-fluoro-4-neopentyl-3-(pyrimidin-2-yloxy)phenyl)pyrazin-2-amine

In a manner similar to that described in Example 320, the title compound was prepared in Step A using neopentylzinc(II) bromide. MS (ESI): mass calculated for _C19H20FN5O : _353.17 ; m/z found: _354.1 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.61 (d, J = 4.8, 2H), 8.26-8.25 (m, 1H), 8.21 (s, 1H), 7.74 (t, J = 7.9, 1H), 7.24 (m,1H), 7.22-7.19(m,1H), 2.53(s,2H), 0.94(s,9H).

Instance 325

2-(3-(5-aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenoxy)pyrimidin-4-amine

In a manner similar to that described in Example 320, the title compound was prepared in Step E using 2-chloropyrimidin-4-amine. MS (ESI): mass calculated for _C20H21FN6O : _380.18 ; m/z found: 381.1 [ _M +H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.26-8.25 (m, 1H), 8.13 (d, J = 1.5, 1H), 8.06 (d, J = 7.0, 1H), 7.80 (m, 1H), 7.32 -7.29(m,1H),6.51(d,J=7.0,1H),2.79-2.71(m,1H),1.89-1.80(m,4H),1.78-1.73(m,1H),1.56-1.47( m,2H), 1.44-1.26(m,3H).

Instance 326

2-(3-(5-aminopyrazin-2-yl)-6-(cyclohexylmethyl)-2-fluorophenoxy)pyrimidin-4-amine

In a manner similar to that described in Example 320, the title compound was prepared in Step A using (cyclohexylmethyl)zinc(II) bromide and in Step E using 2-chloropyrimidin-4-amine. MS (ESI): mass calculated for _C21H23FN6O : _394.19 ; m/z found: _395.1 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.28-8.26 (m, 1H), 8.11 (d, J = 1.5, 1H), 8.05 (d, J = 7.0, 1H), 7.76 (t, J = 7.9, 1H), 7.22-7.19(m, 1H), 6.51(d, J=7.1, 1H), 2.53(d, J=7.2, 2H), 1.73-1.65(m, 5H), 1.60-1.52(m, 1H ), 1.23-1.14(m,3H), 1.04-0.94(m,2H).

Instance 327

2-(3-(5-aminopyrazin-2-yl)-2-fluoro-6-isopentylphenoxy)pyrimidin-4-amine

In a manner similar to that described in Example 320, the title compound was prepared using isopentylzinc(II) bromide in Step A and 2-chloropyrimidin-4-amine in Step E. MS (ESI): mass calculated for _C19H21FN6O : _{368.18 ;} m/z found: 369.1 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.27-8.26 (m, 1H), 8.11 (d, J = 1.5, 1H), 8.05 (d, J = 7.0, 1H), 7.77 (t, J = 7.9, 1H),7.26-7.23(m,1H),6.51(d,J=7.0,1H),2.68-2.62(m,2H),1.62-1.54(m,1H),1.52-1.46(m,2H), 0.91 (d,J=6.5,6H).

Instance 328

2-(3-(5-aminopyrazin-2-yl)-2-fluoro-6-isobutylphenoxy)pyrimidin-4-amine

In a manner similar to that described in Example 320, the title compound was prepared in Step A using isobutylzinc(II) bromide and in Step E using 2-chloropyrimidin-4-amine. MS (ESI): mass calculated for _C18H19FN6O : _{354.16 ;} m/z found: 355.1 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.28-8.26 (m, 1H), 8.12 (d, J = 1.5, 1H), 8.05 (d, J = 7.0, 1H), 7.77 (t, J = 7.9, 1H),7.24-7.21(m,1H),6.50(d,J=7.0,1H),2.53(d,J=7.3,2H),1.97-1.87(m,1H),0.94(d,J=6.6 ,6H).

Example 329

5-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)pyrimidine-2-carboxamide

Using conditions similar to those described in Example 69, the title compound was prepared from 5-bromo-2-cyanopyrimidine. MS (ESI): mass calculated for _C19H17FN6O : _{380.14 ;} m/z found: 381.1 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.56(s, 2H), 8.27(s, 1H), 8.10(d, J=1.5, 1H), 7.88-7.81(m, 1H), 7.40(d, J =8.2,1H), 3.76-3.64(m,1H), 2.33-2.14(m,5H), 2.10-1.97(m,1H), 1.93-1.80(m,1H).

instance 330

5-(4-Cyclobutyl-2-fluoro-3-(thiazolo[4,5-b]pyridin-2-yloxy)phenyl)pyrazin-2-amine

Using conditions similar to those described in Example 69, the title compound was prepared from 2-chlorothiazolo[4,5-b]pyridine. MS (ESI): mass calculated for _C20H16FN5O : _393.11 ; m/z found: 394.0 [ _M +H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ ) δ8.52(dd, J=4.8,1.7,1H),8.45(dd,J=8.0,1.7,1H),8.33-8.28(m,1H),8.03(d ,J=1.5,1H),7.91-7.83(m,1H),7.42-7.34(m,2H),6.72(brs,2H),3.67(p,J=8.9,1H),2.27-2.09(m, 4H), 2.03-1.89 (m, 1H), 1.84-1.73 (m, 1H).

Example 331

5-(4-cyclobutyl-2-fluoro-3-((5-methylthieno[2,3-d]pyrimidin-4-yl)oxy)phenyl)pyrazin-2-amine

The title compound was prepared using similar conditions described in Example 69 from 4-chloro-5-methylthieno[2,3-d]pyrimidine. MS (ESI): mass calculated for _C21H18FN5OS : _407.12 ; m/z found: _408.1 [M+H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ ) δ8.56(s, 1H), 8.29-8.25(m, 1H), 8.01(d, J=1.5, 1H), 7.82-7.76(m, 1H), 7.61( d,J=1.4,1H),7.32(d,J=8.3,1H),6.70(s,2H),3.63-3.53(m,1H),2.66(d,J=1.3,3H),2.31-2.22 (m,1H),2.22-2.12(m,1H),2.10-2.01(m,1H),2.01-1.95(m,1H),1.94-1.84(m,1H),1.78-1.69(m,1H) .

Example 332

N ⁴ -(2-(3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy)ethyl)pyrimidine-2,4-diamine

Using conditions similar to those described in Example 295, the title compound was prepared from 2-amino-4-chloropyrimidine. MS (ESI): mass calculated for _C20H22FN7O : _395.19 ; m/z found: _396.2 [M+H] ⁺ . ¹ H NMR (600MHz, CD ₃ OD) δ8.30-8.24 (m, 1H), 8.03 (d, J = 1.5, 1H), 7.64 (brs, 1H), 7.50-7.43 (m, 1H), 7.19 (d ,J=8.2,1H),5.93(d,J=6.1,1H),4.14(t,J=5.4,2H),3.83(m,1H),3.78-3.67(m,2H),2.31-2.21( m, 2H), 2.17-2.06(m, 2H), 2.05-1.93(m, 1H), 1.87-1.78(m, 1H).

Example 333

3-(5-aminopyrazin-2-yl)-6-ethyl-2-fluorophenol

The title compound was prepared in a manner similar to that described for intermediate K. MS (ESI): mass calculated for _C12H12FN3O : _233.10 ; _m /z found: 234.1 [M+H] ⁺ . ¹ H NMR (CD ₃ OD) δ8.26 (dd, J = 2.3, 1.5Hz, 1H), 8.02 (d, J = 1.5Hz, 1H), 7.12 (dd, J = 8.0, 7.3Hz, 1H), 6.99 -6.93 (m, 1H), 2.68 (q, J=7.5Hz, 2H), 1.21 (t, J=7.5Hz, 3H).

instance 334

5-[4-cyclopentyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

In a manner similar to that described in Example 320, the title compound was prepared using cyclopentylzinc(II) bromide in Step A and 5-bromopyrimidin-2-amine in Step C. MS (ESI): mass calculated for _C19H18FN5O : _351.15 ; m/z found: _352.0 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.61(d, J=4.8Hz, 2H), 8.55(d, J=1.2Hz, 2H), 7.41-7.35(m, 1H), 7.34-7.28(m, 1H), 7.25(t, J=4.8Hz, 1H), 3.25-3.15(m, 1H), 2.00-1.88(m, 2H), 1.87-1.73(m, 2H), 1.71-1.53(m, 4H) .

Example 335

5-{3-[(4-aminopyrimidin-2-yl)oxy]-4-cyclopentyl-2-fluorophenyl}pyrimidin-2-amine. #55672500#

In a manner similar to that described in Example 320, cyclopentylzinc(II) bromide was used in Step A, 5-bromopyrimidin-2-amine in Step C, and 2-chloropyrimidine- 4-Amine Preparation of the title compound. MS (ESI): mass calculated for _C19H19FN6O : _{366.16 ;} m/z found: 367.2 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.45 (d, J = 1.2Hz, 2H), 7.87 (d, J = 5.9Hz, 1H), 7.31–7.27 (m, 1H), 7.26–7.21 (m, 1H), 6.25(d, J=5.9Hz, 1H), 3.26–3.10(m, 1H), 2.04–1.91(m, 2H), 1.85–1.74(m, 2H), 1.70–1.55(m, 4H) .

Instance 336

2-[3-(5-Aminopyrazin-2-yl)-6-cyclopentyl-2-fluorophenoxy]pyrimidin-4-amine

In a manner similar to that described in Example 320, the title compound was prepared in Step A using cyclopentylzinc(II) bromide and in Step E using 2-chloropyrimidin-4-amine. MS (ESI): mass calculated for _C19H19FN6O : _{366.16 ;} m/z found: 367.2 [M+H] ⁺ . ¹ HNMR (500MHz,MeOD)δ8.35–8.21(m,1H),8.04(d,J＝1.5Hz,1H),7.87(d,J＝5.9Hz,1H),7.71–7.57(m,1H) ,7.30–7.17(m,1H),6.24(d,J＝5.9Hz,1H),3.23–3.12(m,1H),2.03–1.89(m,2H),1.88–1.74(m,2H),1.72 –1.52(m,4H).

Instance 337

5-[4-cyclopentyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrazin-2-amine

In a manner similar to that described in Example 320, the title compound was prepared in Step A using cyclopentylzinc(II) bromide. MS (ESI): mass calculated for _C19H18FN5O : _351.15 ; m/z found: _352.2 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.61(d, J=4.8Hz, 2H), 8.24-8.21(m, 1H), 8.11(d, J=1.5Hz, 1H), 7.75-7.70(m, 1H),7.29(dd,J＝8.5,1.4Hz,1H),7.26-7.22(m,1H),3.25-3.10(m,1H),2.01-1.88(m,2H),1.87-1.70(m, 2H), 1.70-1.56 (m, 4H).

Instance 338

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-3-amine

In a manner similar to that described in Example 160, the title compound was prepared from 6-fluoropyridazin-3-amine. MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.1 [M+H] ⁺ . ¹ HNMR (500MHz, MeOD) δ8.26 (dd, J = 2.3, 1.4Hz, 1H), 8.04 (d, J = 1.5Hz, 1H), 7.72–7.61 (m, 1H), 7.25 (d, J = 8.3Hz, 1H), 7.22(d, J=9.4Hz, 1H), 7.08(d, J=9.4Hz, 1H), 3.66(p, J=9.0Hz, 1H), 2.27–2.09(m, 4H) ,2.05–1.93(m,1H),1.87–1.77(m,1H).

Example 339

5-[4-Cyclobutyl-2-fluoro-3-(pyrimidin-2-ylmethoxy)phenyl]pyrazin-2-amine

Using conditions similar to those described in Example 243, the title compound was prepared from 2-(chloromethyl)pyrimidine. MS (ESI): mass calculated for _C19H18FN5O : _351.15 ; m/z found: _352.2 [M+H] ⁺ . ¹ HNMR (500MHz, CD ₃ OD) δ8.84 (d, J = 5.0Hz, 2H), 8.27 (dd, J = 2.4, 1.5Hz, 1H), 8.03 (d, J = 1.5Hz, 1H), 7.52 (dd,J=8.2,7.4Hz,1H),7.48(t,J=5.0Hz,1H),7.24-7.17(m,1H),5.24(s,2H),4.00–3.85(m,1H), 2.33-2.21 (m, 2H), 2.21-2.08 (m, 2H), 2.08-1.94 (m, 1H), 1.92-1.77 (m, 1H).

instance 340

5-{3-[(4-Bromobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine

The title compound was prepared using conditions similar to those described in Example 243 from 1-bromo-4-(bromomethyl)benzene. MS (ESI): mass calculated for _C21H19BrFN3O : _427.07 ; found _m /z: 428.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ 8.29 (dd, J = 2.3, 1.5Hz, 1H), 8.04 (d, J = 1.5Hz, 1H), 7.57-7.52 (m, 2H), 7.52-7.46 ( m,1H),7.43-7.35(m,2H),7.23-7.13(m,1H),5.02(s,2H),3.76(p,J＝8.8Hz,1H),2.32-2.20(m,2H) ,2.20-2.07(m,2H),2.07-1.96(m,1H),1.91-1.77(m,1H).

Instance 341

5-(4-{[3-(5-aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]methyl}phenyl)pyrimidin-2-amine

To a sealable vial was added 5-{3-[(4-bromobenzyl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine (42 mg, 0.098 mmol) and (2 -aminopyrimidin-5-yl)boronic acid (13mg, 0.098mmol), then add 1,4-di Alkane (0.5 mL) and Na ₂ CO ₃ (0.2 mL, 2M). The mixture was bubbled with argon for 10 minutes, then Pd(dppf)Cl2 _{- CH2Cl2 (} 4mg, 0.005mmol) was added and the vial was sealed. The vial was heated at 80 °C for 3 h, then it was cooled to room temperature, and its contents were partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was washed with EtOAc (50 mL) and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to dryness. The resulting residue was purified by preparative HPLC to afford the title compound. MS (ESI): mass calculated for _C25H23FN6O : _442.19 ; m/z found: _443.1 [M+H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.72(s, 2H), 8.30-8.27(m, 1H), 8.10(d, J=1.5Hz, 1H), 7.67-7.62(m, 2H), 7.62- 7.57(m,2H),7.56-7.49(m,1H),7.20(d,J=8.3Hz,1H),5.11(s,2H),3.81(t,J=8.9Hz,1H),2.34-2.22 (m, 2H), 2.21–2.08 (m, 2H), 2.01 (q, J=10.0Hz, 1H), 1.92–1.80 (m, 1H).

instance 342

5-(4-Cyclobutyl-2-fluoro-3-{[4'-(trifluoromethyl)diphenyl-4-yl]methoxy}phenyl)pyrazin-2-amine

The title compound was prepared in a similar manner as described in Example 341 using (4-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calculated for _C28H23F4N3O : _493.18 ; _m /z found: 494.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, MeOD) δ8.32–8.28(m,1H),8.07(d,J＝1.5Hz,1H),7.88–7.81(m,2H),7.78–7.70(m,4H),7.62– 7.57(m,2H),7.51(dd,J=8.2,7.4Hz,1H),7.20(d,J=8.3Hz,1H),5.12(s,2H),3.93–3.74(m,1H),2.35 –2.22 (m, 2H), 2.22 – 2.09 (m, 2H), 2.08 – 1.94 (m, 1H), 1.90 – 1.79 (m, 1H).

Instance 343

5-[4-cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine

Step A: 1-Bromo-3-fluoro-2-(methoxymethoxy)benzene .

To a solution consisting of ₂ -bromo-6-fluorophenol (5.0 g, 26 mmol), DIPEA (9.0 mL, 52.4 mmol) and _CH2Cl2 (131 mL) was added chloro(methoxy)methane (2.2 mL, 29 mmol). The reaction mixture was stirred at room temperature for 1 h, then washed with saturated NaHCO ₃ solution (30 mL). The organic layer was separated, concentrated to dryness, and the resulting residue was purified by FCC to afford the title compound (5.5 g, 89%). ¹ HNMR (500MHz, CDCl ₃ ) δ7.36–7.31(m,1H),7.10–7.03(m,1H),6.97–6.92(m,1H),5.20(s,2H),3.65(s,3H) .

Step B: 1-cyclohexyl-3-fluoro-2-(methoxymethoxy)benzene .

A stir bar, 1-bromo-3-fluoro-2-(methoxymethoxy)benzene (12.9 g, 12.3 mmol) and THF (41 mL) were added to the round bottom flask. Seal the flask with a rubber septum and flush with N for ₅ min. Bis(tri-tert-butylphosphine)palladium(0) (473 mg, 0.92 mmol) was then added to the flask, followed by cyclohexylzinc(II) bromide (0.5M in THF, 37 mL, 19 mmol). The reaction mixture was heated at 60 °C for 1 h, cooled to room temperature, concentrated on silica gel and purified by FCC to afford the title compound (2.4 g, 80%). ¹ HNMR (400MHz, CDCl ₃ ) δ7.02–6.96(m,2H),6.96–6.86(m,1H),5.11(s,2H),3.61(s,3H),3.07–2.97(m,1H) ,1.89–1.77(m,4H),1.46–1.21(m,6H).

Step C: (4-cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)boronic acid .

To a solution of 2,2,6,6-tetramethylpiperidine (3.2 mL, 19 mmol) and THF (40 mL) was added dropwise n-butyllithium (2.3 M in hexane, 8.2 mL, 19 mmol). The reaction mixture was warmed to 0 °C, stirred for 5 min, and then cooled to -78 °C. Triisopropyl borate (4.3 mL, 19 mmol) was added followed by a solution consisting of 1-cyclohexyl-3-fluoro-2-(methoxymethoxy)benzene (3.0 g, 13 mmol) and THF (20 mL). The solution. The mixture was stirred at -78 °C for 5 min, warmed to room temperature, and quenched with saturated _NH4Cl (20 mL). The mixture was partitioned between water (20 mL) and EtOAc (40 mL). The organic phase was separated and the aqueous solution was further extracted with EtOAc (2 x 40 mL). The organic extracts were combined, concentrated to dryness and the crude product was used directly.

Step D: 5-(4-cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)pyrimidin-2-amine .

(4-cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)boronic acid (1.4g, 5.0mmol), 2-amino-5-bromopyrimidine (0.95g, 5.5mmol) and THF (25 mL) was bubbled with _N2 for 10 min. A solution of Na ₂ CO ₃ (25 mL, 50 mmol, 2M) was then added, and the mixture was further bubbled with N ₂ for 20 min. 1,1"bis(di-tert-butylphosphino)ferrocenepalladium dichloride (162mg, 0.25mmol) was added, the reaction mixture was heated at 50°C for 2h, cooled to room temperature and diluted with EtOAc (50mL). The organic phase was Isolation, concentration on silica, and purification by FCC afforded the title compound (0.84 _g , 51%). MS (ESI): Mass calculated for _Ci8H22FN3O2 : _331.17 ; _m /z found : 332.3[M+H] ⁺ .

Step E: 3-(2-aminopyrimidin-5-yl)-6-cyclohexyl-2-fluorophenol .

To a solution consisting of 5-(4-cyclohexyl-2-fluoro-3-(methoxymethoxy)phenyl)pyrimidin-2-amine (840 mg, 2.5 mmol) and CH ₂ Cl ₂ (25 mL) TFA (0.6 mL, 7.6 mmol) was added and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was then diluted with _{CH2Cl2 (} 95 mL) and washed with a saturated solution of _NaHCO3 (50 mL). The organic layer was separated, concentrated to dryness, and the resulting residue was purified by FCC to afford the title compound.

Step F: 5-[4-cyclohexyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]pyrimidin-2-amine .

Add 3-(2-aminopyrimidin-5-yl)-6-cyclohexyl-2-fluorophenol (100mg, 0.35mmol), 2-chloropyrimidine (42mg, 0.35mmol), K ₂ CO ₃ (96 mg, 0.70 mmol), 18-crown-6 (5 mg, 0.02 mmol) and DMA (0.5 mL). The vial was capped and irradiated in a microwave reactor at 110 °C for 10 min, then cooled to room temperature and diluted with EtOAc (10 mL) and water (5 mL). The organic layer was separated, concentrated to dryness, and the resulting residue was purified by preparative HPLC to afford the title compound (65 mg, 39%). MS (ESI): mass calculated for _C20H20FN5O : _365.17 ; m/z found: 366.1 [ _M +H] ⁺ . ¹ HNMR (400MHz, CD ₃ OD) δ8.62 (d, J = 4.8Hz, 2H), 8.56 (d, J = 1.2Hz, 2H), 7.44–7.36 (m, 1H), 7.30 (dd, J = 8.3,1.4Hz,1H),7.26(t,J＝4.8Hz,1H),2.85–2.70(m,1H),1.86–1.64(m,5H),1.59–1.39(m,2H),1.35–1.21 (m,3H).

instance 344

5-{3-[(4-aminopyrimidin-2-yl)oxy]-4-cyclohexyl-2-fluorophenyl}pyrimidin-2-amine

Using conditions similar to those described in Example 343, the title compound was prepared in Step F from 4-amino-2-chloropyrimidine. MS (ESI): mass calculated for _C20H21FN6O : _380.18 ; m/z found: 381.1 [ _M +H] ⁺ . ¹ H NMR (400MHz, CD ₃ OD) δ8.44 (d, J = 1.4Hz, 2H), 7.87 (d, J = 6.0Hz, 1H), 7.34–7.26 (m, 1H), 7.22 (d, J = 8.3Hz, 1H), 6.25(d, J=6.0Hz, 1H), 2.84–2.68(m, 1H), 1.87–1.65(m, 5H), 1.52–1.20(m, 5H).

instance 345

3-(5-aminopyrazin-2-yl)-6-cyclohexyl-2-fluorophenol.

In a manner similar to that described in Steps AD of Example 320, the title compound was prepared in Step A using cyclohexylzinc(II) bromide. MS (ESI): mass calculated for C16H18FN3O: _287.14 ; m/z found: _288.1 [ _M +H] ⁺ . ¹ HNMR (500MHz, CDCl ₃ ) δ8.47-8.45 (m, 1H), 8.09 (d, J = 1.5Hz, 1H), 7.36-7.29 (m, 1H), 7.06-7.03 (m, 1H), 5.60 (d,J=6.3Hz,1H),4.65(s,2H),3.00-2.92(m,1H),1.94-1.81(m,4H),1.80-1.74(m,1H),1.52-1.38(m ,4H), 1.33-1.25(m,1H).

Instance 346

3-(5-aminopyrazin-2-yl)-6-(cyclohexylmethyl)-2-fluorophenol.

In a manner similar to that described in Steps AD of Example 320, the title compound was prepared in Step A using (cyclohexylmethyl)zinc(II) bromide. ¹ HNMR (500MHz, CDCl ₃ ) δ8.47-8.45 (m, 1H), 8.09 (d, J = 1.5Hz, 1H), 7.30-7.26 (m, 1H), 6.95-6.93 (m, 1H), 5.62 (s,1H),4.66(s,2H),2.56(d,J＝7.1Hz,2H),1.74-1.58(m,7H),1.23-1.13(m,3H),1.05-0.94(m,2H ).

Instance 347

5-{3-[(2-Aminopyridin-4-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine.

The title compound was prepared from 2-amino-4-bromopyridine using conditions similar to those described in Example 164 using DMSO as solvent and heating by microwave irradiation at 140°C for 10 hours. MS (ESI): mass calculated for _C19H18FN5O : _351.15 ; m/z found: _352.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.49–8.46 (m, 1H), 8.09 (d, J=1.5Hz, 1H), 7.93 (d, J=5.9Hz, 1H), 7.83–7.76 (m, 1H ),7.24(d,J=8.3Hz,1H),6.30–6.24(m,1H),5.89(d,J=2.2Hz,1H),4.71(s,2H),4.40(s,2H),3.64 –3.53 (m, 1H), 2.29 – 2.07 (m, 4H), 2.03 – 1.90 (m, 1H), 1.87 – 1.76 (m, 1H).

Instance 348

5-{3-[(6-aminopyrazin-2-yl)oxy]-4-cyclobutyl-2-fluorophenyl}pyrazin-2-amine.

The title compound was prepared from 2-amino-6-chloropyrazine using conditions similar to those described in Example 164, using DMSO as solvent and heating by microwave irradiation at 140°C for 6 hours. MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.1 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-d ₆ )δ8.28–8.24(m,1H),8.00(d,J＝1.5Hz,1H),7.72–7.65(m,1H),7.55(d,J＝3.8Hz ,2H),7.26(d,J＝8.3Hz,1H),6.70(s,2H),6.51(s,2H),3.60–3.47(m,1H),2.22–2.03(m,4H),1.99– 1.85(m,1H),1.83–1.70(m,1H).

Example 349

5-[4-cyclobutyl-2-fluoro-3-(pyrimidin-5-yloxy)phenyl]pyrazin-2-amine.

The title compound was prepared from 5-bromopyrimidine using conditions similar to those described in Example 164, using DMSO as solvent and heating by microwave irradiation at 140°C for 2 hours. MS (ESI): mass calculated for _C18H16FN5O : _337.13 ; m/z found: _338.1 [M+H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ8.94(s, 1H), 8.46–8.42(m, 1H), 8.40(s, 2H), 8.09(d, J=1.5Hz, 1H), 7.87–7.80(m ,1H),7.31–7.27(m,1H),4.78(s,2H),3.69–3.58(m,1H),2.30–2.10(m,4H),2.07–1.92(m,1H),1.90–1.76 (m,1H).

Instance 350

6-[3-(5-Aminopyrazin-2-yl)-6-cyclobutyl-2-fluorophenoxy]pyridazin-4-amine.

The title compound was prepared from 6-chloro-4-pyridazinamine using conditions similar to those described in Example 164 using DMSO as solvent and heating by microwave irradiation at 180°C for 2 hours. MS (ESI): mass calculated for _C18H17FN6O : _{352.14 ;} m/z found: 353.1 [M+H] ⁺ . ¹ HNMR (500MHz, DMSO-d ₆ )δ8.32(d, J=2.0Hz, 1H), 8.25(s, 1H), 8.04–7.97(m, 1H), 7.74–7.67(m, 1H), 7.26 (d,J=8.3Hz,1H),6.68(s,2H),6.60(s,2H),6.23(d,J=2.0Hz,1H),3.58–3.46(m,1H),2.17–2.02( m,4H), 1.98–1.84(m,1H), 1.80–1.69(m,1H).

instance 351

5-[4-tert-butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3-b]pyridine

Step A: (3-Bromo-6-(tert-butyl)-2-fluorophenoxy)(tert-butyl)dimethylsilane.

To a 100 mL round bottom flask was added a stir bar, THF (38.0 mL), tert-butyl(2-(tert-butyl)-6-fluorophenoxy)dimethylsilane (5.0 g, 18 mmol) and N,N, N',N'-Tetramethylethylenediamine (1.6 mL, 19 mmol). The flask was cooled to -78°C and then treated with sec-butyllithium (14 mL, 20 mmol, 1.4M in hexane) for 6 min. The resulting mixture was stirred for 2 hours, then treated with a solution consisting of carbon tetrabromide (8.7 mL, 26 mmol) and THF (8.0 mL) over 2 min. The resulting mixture was stirred at -78 °C for another 2 h. The reaction mixture was then warmed to room temperature and stirred for an additional 18 h. Then the reaction mixture was poured into saturated _NH4Cl solution and extracted with EtOAc (200 mL). The organic phase was separated, dried _{over Na2SO4} , filtered and concentrated to dryness. Purification by FCC yielded the title compound.

Step B: 3-bromo-6-(tert-butyl)-2-fluorophenol.

Into a 100 mL round bottom flask was added a stir bar, (3-bromo-6-(tert-butyl)-2-fluorophenoxy)(tert-butyl)dimethylsilane (6.4 g, 18 mmol), THF (44.0 mL ) and TBAF (25.0 g, 24.0 mmol, 1 M in hexane). The mixture was stirred for 2 hours, then poured into _NH4Cl (100 mL, saturated solution). The aqueous mixture was then extracted with EtOAc (200 mL), the organic extracts _were dried over _Na2SO4 , filtered and concentrated to dryness. Purification by FCC yielded the title compound.

Step C: 2-(3-Bromo-6-(tert-butyl)-2-fluorophenoxy)pyrimidine.

Add a stir bar, 3-bromo-6-(tert-butyl)-2-fluorophenol (1.4 g, 5.7 mmol), 2-chloropyrimidine (0.76 g, 6.3 mmol), cesium carbonate (3.6 g , 11 mmol) and acetonitrile (11.0 mL). The mixture was heated at 80°C for 18 hours. The reaction mixture was filtered and the filtrate was directly subjected to FCC to afford the title compound (0.95 g, 51%). ¹ HNMR (400MHz, CDCl ₃ ) δ8.58 (d, J=4.8Hz, 2H), 7.37 (dd, J=8.8, 6.7Hz, 1H), 7.12 (dd, J=8.8, 1.9Hz, 1H), 7.09–7.05 (m, 1H), 1.35 (s, 9H).

Step D: 5-[4-tert-Butyl-2-fluoro-3-(pyrimidin-2-yloxy)phenyl]-1H-pyrrolo[2,3-b]pyridine Pyridine

In a similar manner to step D of intermediate A, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo [2,3-b]pyridine was coupled to 2-(3-bromo-6-(tert-butyl)-2-fluorophenoxy)pyrimidine to afford the title compound (10 mg, 8%). MS (ESI): mass calculated for _C21H19FN4O : _362.15 ; m/z found: 363.1 [M ₊ H] ⁺ . ¹ HNMR (400MHz, CDCl ₃ ) δ10.11(s, 1H), 8.60(d, J=4.8Hz, 2H), 8.53-8.46(m, 1H), 8.15-8.08(m, 1H), 7.40-7.30 (m, 3H), 7.11-7.01 (m, 1H), 6.53 (dd, J=3.5, 1.8Hz, 1H), 1.45-1.41 (m, 9H).

Examples 1-36, summarized below in Table 4, are hypothetical and, unless otherwise indicated, can be readily synthesized by those skilled in the art using the above reaction schemes or by synthetic routes known to those skilled in the art. Based on the compounds disclosed in the present invention, those skilled in the art will deduce the following hypothetical compounds with activity on FLAP.

Table 4 hypothetical example

D) General administration, formulation and dosage

The present invention provides substituted heteroaryl ketone compounds useful as FLAP modulators.

The invention features a method for treating a subject suffering from a FLAP-mediated disease and/or disorder in need thereof comprising administering to the subject a therapeutically effective amount of a compound of the invention. In particular, the present invention also provides methods for treating or inhibiting the progression of FLAP-mediated diseases and/or disorders or their associated symptoms or complications in subjects suffering from such diseases and/or disorders, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of the invention.

Embodiments of the invention include methods wherein the compound of formula (I) is a FLAP modulator.

Embodiments of the invention include the use of compounds of formula (I) in the manufacture of a medicament for the treatment of FLAP-mediated diseases and/or disorders.

Embodiments of the invention include the use of compounds of formula (I) as medicaments.

Compounds of formula (I) have a FLAP modulating effect and are useful, for example, as therapeutic agents for the following FLAP-mediated diseases and/or disorders or associated symptoms or complications: respiratory disorders, cardiac or cardiovascular diseases, autoimmune disorders, carcinogenesis and their associated symptoms or complications.

The compounds of formula (I) can be administered orally or parenterally, and when formulated for the intended route of administration, they are useful as therapeutic agents for the treatment of FLAP-mediated diseases and/or disorders. FLAP-mediated diseases and/or disorders include, but are not limited to, diseases and/or disorders associated with leukotriene synthesis pathways, and thus can be treated, managed or in some cases prevented by treatment with compounds of the invention.

One aspect of the present invention provides a method for treating diseases and/or disorders or their associated symptoms or complications in response to modulation of FLAP in a subject in need thereof, the method comprising administering to the subject A therapeutically or prophylactically effective amount of a compound of formula (I) or a form thereof.

Another aspect of the present invention provides a method for treating a disease and/or disorder selected from the group consisting of respiratory disease and/or disorder, cardiac and cardiovascular disease and/or disorder, in a subject in need thereof, Autoimmune diseases and/or disorders, carcinogenesis and their related symptoms or complications, the method comprises administering a therapeutically or prophylactically effective amount of a compound of formula (I) or a form thereof to a subject.

More particularly, the present invention relates to the treatment of exacerbated, non-allergic asthma, aspirin aggravated respiratory disease, pulmonary hypertension, fibrotic lung disease, acute respiratory distress syndrome, obstructive sleep apnea and chronic obstructive pulmonary disease or their A method of related symptoms or complications in a subject of such diseases and/or disorders, wherein the method comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of formula (I) or a form thereof.

Furthermore, the present invention relates to the treatment of myocardial infarction, atherosclerosis and coronary artery disease, stroke, aortic aneurysm, atherosclerosis or their associated symptoms or complications in subjects suffering from such diseases and/or disorders , wherein the method comprises administering to a subject a therapeutically or prophylactically effective amount of a compound of formula (I) or a form thereof.

In addition, the present invention also relates to the treatment of rheumatoid arthritis, inflammatory bowel disease, nephritis, spondyloarthritis, polymyositis, dermatomyositis, gouty exudate, systemic lupus erythematosus, systemic sclerosis, Alzheimer's Disease, multiple sclerosis, allergic rhinitis, chronic sinusitis, allergic dermatitis and asthma, wherein the method comprises administering to the subject a therapeutically or prophylactically effective amount of a compound of formula (I) or a form thereof.

Finally, the present invention also relates to a method for treating tumor cell proliferation, differentiation and apoptosis, tumor-associated angiogenesis, and metastasis and invasion of cancer cells, wherein the method comprises administering a therapeutically or prophylactically effective amount of the formula (I ) compounds or forms thereof.

Another aspect of the invention provides a pharmaceutical composition comprising at least one compound of formula (I) or a form thereof and a pharmaceutically acceptable carrier.

The invention also features a method for treating a subject suffering from a FLAP-mediated disease and/or disorder in need thereof comprising administering to the subject a therapeutically effective amount of a drug comprising at least one of the present invention. Pharmaceutical compositions of compounds of the invention.

In addition, another aspect of the present invention relates to the use of compounds of formula (I) or forms thereof for the manufacture of medicaments useful for the treatment of FLAP-mediated diseases and/or disorders in a subject in need thereof.

In the clinical use of the compound of the present invention, pharmaceutically acceptable additives may be added thereto to prepare various formulations according to their intended administration routes, and the formulations may be administered.

Various additives commonly used in the field of pharmaceutical compositions can be used herein, including, for example, gelatin, lactose, sucrose, titanium dioxide, starch, crystalline cellulose, methylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose , Corn Starch, Microcrystalline Wax, White Petrolatum, Magnesium Metasilicate, Calcium Phosphate Anhydrous, Citric Acid, Trisodium Citrate, Hydroxypropyl Cellulose, Sorbitol, Sorbitan Fatty Acid Ester, Polysorbate Alcohol Esters, Sucrose Fatty Acid Esters, Polyethylene Glycol, Hardened Castor Oil, Polyvinylpyrrolidone, Magnesium Stearate, Palmitoleic Acid, Light Silicic Anhydride, Talc, Vegetable Oil, Benzyl Alcohol, Gum Arabic, Propylene Glycol, Polyalkylene Diols, Cyclodextrins and Hydroxypropyl Cyclodextrins.

The compound of the present invention combined with such additives can be formulated into various preparation forms, for example solid preparations such as tablets, capsules, granules, powders and suppositories; and liquid preparations such as syrups, elixirs and injections. These formulations may be prepared by any method known in the art of pharmaceutical compositions. Liquid preparations may be in the form of being dissolved or suspended in water or any other suitable medium before use. Specifically for injections, the preparations can be dissolved or suspended in physiological saline or glucose solution, and buffers and preservatives can be added thereto, if necessary.

The compounds of the present invention are effective in animals, including humans and other mammals. Any ordinary physician, veterinarian or clinician can readily determine the necessity, if any, of treatment with the compounds of the invention.

Those skilled in the treatment of diseases and/or disorders mediated by FLAP, or their associated symptoms or complications, can determine the effective daily amount from the test results and other information presented hereinafter. As is well known to those skilled in the art, the exact dosage and frequency of administration will depend on the particular compound of the invention used, the particular disease and/or disorder being treated or their associated symptoms or complications, the disease and/or disorder being treated or They relate to the severity of symptoms or complications, the age, weight and general condition of the particular patient, and other medications the patient may be taking. Furthermore, it will be apparent that said effective daily amount may be lowered or increased depending on the response of the patient receiving treatment and/or according to the evaluation of the physician prescribing the compounds of the invention. The effective daily dose ranges mentioned herein are therefore only guidelines for practicing the invention.

Preferably, the methods for treating FLAP diseases and/or disorders described herein employ any of the compounds defined herein, in dosage forms containing a pharmaceutically acceptable carrier comprising from about 1 mg to about 1000 mg ; in particular from about 0.5 mg to about 500 mg of the compound, and the dosage form may be configured in any form suitable for the chosen mode of administration. Dosages may, however, vary depending on the requirements of the subject, the severity of the disease and/or disorder being treated or their associated symptoms or complications, and the compound employed. Daily administration or post-cycle dosing may be employed.

When the compounds of the present invention are put into clinical use, for example, the dosage and the frequency of its administration may vary with the sex, age, weight and condition of the patient and the desired type and extent of treatment with the compound. For oral administration, generally, compound dosages may range from about 0.01 mg/kg/day to about 100 mg/kg body weight/day or in the range of about 0.03 mg/kg/day to about 1 mg/kg/day. The frequency of oral administration is preferably one to several times per day. For parenteral administration, the dosage may be in the range of about 0.001 mg/kg/day to about 10 mg/kg/day, in the range of about 0.001 mg/kg/day to about 0.1 mg/kg/day or in the In the range of about 0.01 mg/kg/day to about 0.1 mg/kg/day. The frequency of parenteral administration is preferably one to several times per day. For oral administration, the composition is preferably provided in the form of a tablet containing from about 1.0 mg to about 1000 mg of active ingredient, in particular 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg , 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 750 mg, 800 mg, 900 mg and 1000 mg of the active ingredient to adjust the dose according to the symptoms of the subject to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.

General physicians, veterinarians and clinicians can readily determine the effective dosage of a pharmaceutical compound required to treat, prevent, inhibit, slow or arrest a desired disease, and can readily treat afflicted patients with the compound.

The pharmaceutical composition of the present invention will contain about 0.001 mg/kg/day to about 10 mg/kg/day per unit dosage unit (for example, per tablet, per capsule, per powder, per injection, per suppository, per teaspoon, etc. days (particularly from about 0.01 mg/kg/day to about 1 mg/kg/day; and more particularly from about 0.1 mg/kg/day to about 0.5 mg/kg/day), and may be given at about 0.001 mg/kg/day to about 30 mg/kg/day (especially about 0.01 mg/kg/day to about 2 mg/kg/day, more especially about 0.1 mg/kg/day to about 1 mg/kg/day, even more especially about 0.5 mg /kg/day to about 1 mg/kg/day).

Preferably these compositions are in unit dosage form such as tablets, pills, capsules, dry powders for reconstitution or inhalation, granules, lozenges, sterile parenteral solutions or suspensions, metered dose aerosols or Liquid spray, drops, ampoules, autoinjector device, or suppository for oral, nasal, sublingual, intraocular, transdermal, parenteral, rectal, vaginal, dry powder inhaler Administration or other routes of inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for administration from 1 to 4 times per day, preferably once or twice per day; Depot formulation for injection.

The formulations may contain the compound of the invention in an amount ranging from about 1.0 to about 100% by weight of the formulation, or in the range of about 1.0 to about 60% by weight. The formulation may contain any other therapeutically effective compound.

The present invention includes within its scope prodrugs of the compounds of the invention. Generally, such prodrugs will be functional derivatives of the compound, which can be readily converted in vivo to the desired compound. Thus, in the methods of treatment of the present invention, the term "administration" shall encompass the treatment of a variety of said compounds with a specifically disclosed compound or with a compound which may not be specifically disclosed but which is converted in vivo to a specified compound after administration to a subject. obstacle. General procedures for selecting and preparing suitable prodrug derivatives are described, for example, in "Design of Prodrugs ", edited by H. Bundgaard, Elsevier, 1985.

Some of the crystalline forms of the compounds may exist as polymorphs and are likewise intended to be encompassed by the present invention. In addition, some compounds may form solvates with water (eg, hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of the present invention.

If the processes used to prepare the compounds according to the invention result in mixtures of stereoisomers, these isomers can be separated by conventional techniques such as preparative chromatography. Compounds may be prepared in racemic form either by stereospecific synthesis or by resolution as individual enantiomers or diastereomers. A compound can be resolved, for example, into its component enantiomers or diastereomers by standard techniques, for example by formation of a salt with an optically active base to form stereoisomer pairs, followed by fractional crystallization and regeneration of the free acid. Compounds can also be resolved by formation of stereoisomeric esters or amides followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds can be resolved on a chiral HPLC column. It is to be understood that all stereoisomers, racemic mixtures, diastereomers, cis-trans isomers and their enantiomers are encompassed within the scope of the present invention.

E) Usage

dose

To prepare pharmaceutical compositions such as tablets, the main active ingredient is mixed with pharmaceutically acceptable carriers such as conventional tableting ingredients such as diluents, binders, binders, disintegrants, lubricants, antiadherents and glidants . Suitable diluents include, but are not limited to, starch (i.e., hydrolyzable corn, wheat, or potato starch), lactose (granulated, spray-dried, or anhydrous), sucrose, sucrose-based diluents (sugar for confectionery; sucrose plus About 7 to 10% by weight invert sugar; sucrose plus about 3% by weight modified dextrin; sucrose plus invert sugar, about 4% by weight invert sugar, about 0.1 to 0.2% by weight cornstarch and stearic acid magnesium), dextrose, inosose, mannitol, sorbitol, microcrystalline cellulose (ie AVICEL ^TM microcrystalline cellulose from FMC Corporation), calcium hydrogen phosphate, calcium sulfate dihydrate, calcium lactate trihydrate Hydrate etc. Suitable binders and binders include, but are not limited to, gum arabic, guar, tragacanth, sucrose, gelatin, glucose, starch, and cellulose (i.e., methylcellulose, sodium carboxymethylcellulose, ethyl cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, etc.), water-soluble or water-dispersible binders (such as alginic acid and its salts, magnesium aluminum silicate, hydroxyethylcellulose [that is obtained from TYLOSE ^(TM) of Hoechst Celanese], polyethylene glycol, polysaccharide acid, bentonite, polyvinylpyrrolidone, polymethacrylate and pregelatinized starch) and the like. Suitable disintegrants include, but are not limited to, starch (corn, potato, etc.), sodium starch glycolate, pregelatinized starch, clay (magnesium aluminum silicate), cellulose (such as croscarmellose sodium and microcrystalline cellulose), alginates, pregelatinized starches (i.e. corn starch, etc.), gums (i.e. agar, guar, locust bean, karaya, pectin and tragacanth), cross-linked polyvinylpyrrolidone, etc. Suitable lubricants and anti-tacking agents include, but are not limited to, stearates (magnesium stearate, calcium stearate, and sodium stearate), stearic acid, talc, waxes, stearowet, boric acid, sodium chloride, DL -Leucine, carbowax4000, carbowax6000, sodium oleate, sodium benzoate, sodium acetate, sodium lauryl sulfate, magnesium lauryl sulfate, etc. Suitable glidants include, but are not limited to, talc, cornstarch, silica (i.e., CAB-O-SIL ^™ silica from Cabot, SYLOID™ silica from WR Grace/Davison, and SYLOID ^™ silica from Degussa). AEROSIL ^TM silicon dioxide) and the like. Sweetening and flavoring agents can be added to chewable solid dosage forms to improve the palatability of the oral dosage form. In addition, colorants and coating agents may be added or coated to solid dosage forms for easy identification of the drug or for aesthetic purposes. These carriers are formulated with the pharmaceutical active to provide precise, appropriate dosages of the pharmaceutical active with therapeutic release characteristics.

These carriers are usually mixed with the pharmaceutically active substance to form a solid preformulation composition containing a homogeneous mixture of the pharmaceutically active substance forms of the invention or their pharmaceutically acceptable salts. Preformulations will generally be formed by one of three common methods: (a) wet granulation, (b) dry granulation and (c) dry blending. When these preformulation compositions are referred to as homogeneous, it is meant that the active ingredient is dispersed uniformly throughout the composition so that the composition can be readily subdivided into equivalent dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from about 0.1 mg to about 500 mg of the active ingredient of the invention. Tablets or pills containing the novel compositions may also be formulated as multi-layered tablets or pills to provide sustained release products or to provide dual release products. For example, a dual release tablet or pill may comprise an inner dosage component and an outer dosage component, the latter in the form of an envelope covering the former. The two components can be separated by an enteric layer, which prevents disintegration in the stomach, and then allows the inner component to enter the duodenum intact or delay drug release. A variety of materials can be used for such enteric layers or coatings, such materials including various polymeric materials such as shellac, cellulose acetate (i.e. cellulose acetate phthalate, cellulose acetate trimellitate), poly Vinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, methacrylate and ethacrylate copolymer, methacrylic acid esters and methyl methacrylate copolymers, etc. It can also be obtained by coating with a substance that is sparingly soluble or insoluble in solution (for wet granulation, which acts as a binder) or a low-melting solid in molten form (in wet granulation, which can incorporate the active ingredient) or Wet granulation to make sustained release tablets. These materials include natural and synthetic polymeric waxes, hydrogenated oils, fatty acids and alcohols (i.e., beeswax, carnauba wax, cetyl alcohol, cetearyl alcohol, etc.), fatty acid esters, metallic soaps, and other acceptable Materials used to granulate, coat, entrap or otherwise limit the solubility of active ingredients to obtain long-acting or sustained-release products.

Liquid forms that may be added to the novel compositions of the present invention for oral or injection administration include, but are not limited to, aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, edible oils such as cottonseed oil, sesame oil, coconut oil or Flavored emulsions in peanut oil, as well as elixirs and similar medicinal vehicles. Suitable suspending agents for aqueous suspensions include synthetic and natural gums such as acacia, agar-agar, alginates (i.e., propylene alginate, sodium alginate, etc.), guar gum, karaya gum, Locust bean gum, pectin, tragacanth, and xanthan gum), celluloses (such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, and hydroxypropyl methylcellulose and their combinations), synthetic polymers (such as polyvinylpyrrolidone, carbomer (ie carbopol) and polyethylene glycol), clays (such as bentonite, hectorite, green slope Gordolith or sepiolite), and other pharmaceutical suspending agents (such as lecithin, gelatin, etc.). Suitable surfactants include, but are not limited to, docusate sodium, sodium lauryl sulfate, polysorbate, octylphenol-9, nonylphenol-10, polysorbate 20, polysorbate Alcohol ester 40, polysorbate 60, polysorbate 80, polyoxamer 188, polyoxamer 235 and combinations thereof. Suitable deflocculants or dispersants include pharmaceutical grade lecithin. Suitable flocculants include, but are not limited to, simple neutral electrolytes (such as sodium chloride, potassium chloride, etc.), highly charged insoluble polymers and polymer electrolyte substances, water-soluble divalent or trivalent ions (such as calcium salts, alum Or sulfates, citrates and phosphates (which can be used as both pH buffering agent and flocculant in the formulation). Suitable preservatives include but are not limited to parabens (such as methyl esters, ethyl esters , n-propyl and n-butyl esters), sorbic acid, sodium ethylmercury thiosalicylate, quaternary ammonium salts, benzyl alcohol, benzoic acid, chlorhexidine gluconate, phenylethyl alcohol, etc. Can be used in liquid pharmaceutical formulations There are many vehicles, but the liquid vehicle used in a particular dosage form must be compatible with the suspending agent. For example, non-polar liquid vehicles such as fatty esters and oily liquid vehicles are best combined with liquid vehicles such as low HLB (hydrophilic-lipophilic). Equilibrium value) surfactants, hectorite stearyl dimethyl benzyl ammonium, water-insoluble resins, water-insoluble film-forming polymers, etc. are used together. On the contrary, polar liquids such as water, alcohol , polyols and glycols are best used with suspending agents such as higher HLB surfactants, clays, silicates, gums, water-soluble celluloses, water-soluble polymers, etc. For parenteral administration , sterile suspensions and solutions are desirable. Liquid forms that can be used for parenteral administration include sterile solutions, emulsions, and suspensions. When intravenous administration is desired, the use of such liquids usually contains a suitable preservative. Osmotic preparation.

Additionally, the compounds of the present invention may be administered in intranasal dosage form through the use of suitable intranasal vehicles or via transdermal skin patches, compositions of which are well known to those of ordinary skill in the art. To be administered in the form of a transdermal delivery system, the administration of the therapeutic dose will, of course, be continuous rather than intermittent throughout the dosage regimen.

Compounds of the invention can also be administered in the form of liposomal delivery systems (eg, small unilamellar vesicles, large unilamellar vesicles, multilamellar vesicles, etc.). Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, phosphatidylcholines, and the like.

The daily dosage of the pharmaceutical composition of the present invention may vary widely from about 0.1 mg to about 5000 mg; preferably, for an average human being, the daily dosage will be in the range of about 1 mg to about 100 mg. For oral administration, the composition is preferably presented in the form of a tablet containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 or 500 mg of the active ingredient, expressed as The dosage is adjusted according to the symptoms of the subject to be treated. Advantageously, the compounds of the invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

It will also be apparent to those skilled in the art that a therapeutically effective dose of an active compound of the invention, or a pharmaceutical composition thereof, will vary with the desired effect. Optimum dosages to be administered can thus be readily determined by those skilled in the art and will vary with the particular compound employed, the mode of administration, the strength of the formulation and the advancement of the disease condition. In addition, factors associated with the particular subject being treated, including subject age, weight, diet and time of administration, will result in the need to adjust dosages to appropriate therapeutic levels. Accordingly, the above dosages are exemplary of what is typically the case. There can, of course, be individual instances where higher or lower dosage ranges should be employed, and such instances are within the scope of this invention.

When it is desired to use the compounds of the invention as modulators of FLAP in a subject in need thereof, the compounds of the invention may be administered in any of the aforementioned compositions and dosage regimens or by those compositions and dosage regimens established in the art apply.

In their use, the compounds of the invention may be combined with any other therapeutic agent useful in the treatment of FLAP-mediated disorders.

Combinations include not only combinations of a compound of the invention with one other active substance, but also combinations of a compound of the invention with two or more other active substances or non-drug therapies. The range of feasible combinations of the compounds of the invention with one, two or more active substances is within the knowledge of a person skilled in the art in the treatment of FLAP-mediated disorders.

In particular, combinations of FLAP modulators with prostaglandin modulators, cyclooxygenase-1 modulators or cyclooxygenase-2 modulators are useful in the treatment of inflammatory and autoimmune diseases and/or disorders as well as cardiovascular diseases and/or disorders or vascular injury (Z.Yu et al., "Disruption of the5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2deletioninmice," Proc.Natl.Acad.Sci.USA, 2012,109(17), 6727-32; Z.Yu et al., "MyeloidCell5-Lipoxygenase Activating Protein lar "Circ. Res., 2012, Epub Dec. 18). Due to the synergistic effect of histamine and leukotrienes, combinations of FLAP modulators and histamine receptor 1 or 4 antagonists are useful in the treatment of respiratory, allergic, dermatological and autoimmune disorders (A. Reicin et al. "Montelukast, aleukotriereceptorantagonist, combination with loratadine, ahistaminereceptorantagonist, in the treatment of chronic asthma," Arch. Intern. Med., 2000, 160(16), 2418-88; , 2005, 297(3), 134-38).

preparation

To prepare the pharmaceutical composition of the present invention, one or more compounds of formula (I) or their salts as active ingredients are closely mixed with pharmaceutical carriers according to conventional pharmaceutical compounding techniques, and the carrier can be in various forms, This will depend on the form of preparation desired for administration, eg oral or parenteral. Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in The Handbook of Pharmaceutical Excipients published by the American Pharmaceutical Association and Pharmaceutical Society of Great Britain.

For administration purposes, the compounds of the present invention may be formulated into various pharmaceutical forms. Methods of formulating pharmaceutical compositions are described in various publications, such as Pharmaceutical DosageForms: Tablets, Second Revised Supplement, Vols 1-3, edited by Lieberman et al; Pharmaceutical DosageForms: Parenteral Medications , Vols 1-2, Avis eds.; and Pharmaceutical Dosage Forms: Disperse Systems , Volumes 1-2, edited by Lieberman et al.; Published by Marcel Dekker, Inc.

F) Biological examples

The following procedure is used to determine the ability of compounds of the invention to treat FLAP-mediated diseases and/or disorders or their associated symptoms or complications. Binding assay data represent mean values obtained from two different assay plates, with samples run in duplicate on each plate. Human whole blood assay data represent a single replicate on an assay plate using whole blood from at least one healthy donor.

FLAP binding assay

Compounds were tested for modulating activity on FLAP using the following assay. Human and murine FLAP-encoding DNA were amplified by polymerase chain reaction and cloned into pFastBac1 (Invitrogen) with an NH2-terminal 6-His tag for expression in Spodoptera frugiperda (Sf-9) cells. FLAP-containing membranes were prepared as FITC-labeled FLAP modulator (3-(3-(tert-butylthio)-1-(4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)- 1H-indol-2-yl)-2,2-dimethylpropanoic acid). FLAP binding assays were performed in HTRF format (Homogeneous Time-Resolved Fluorescence). FLAP-containing membranes (finally 1 μg/well for humans) were treated in the presence of the HTRF ligand, [5-[({[2-(2-{3-[3-(tert-butylsulfanyl)-1-( 4-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionyl}hydrazino)-2-oxoethyl ]sulfanyl}acetyl)amino]-2-(6-hydroxy-3-oxo-3H-oxanthene-9-yl)benzoic acid] (final 25nM), terbium-labeled anti-His tag antibody (final 0.5 ng/well, obtained from Cisbio) and incubated with compounds. The reaction was allowed to proceed for 2 hours before reading the plate in HTRF mode on an Envision plate reader. Data are expressed as HTRF ratios.

For the human FLAP binding assay, data were analyzed with 3DXExplorer software. Ratios were calculated as the ratio of relative light units at 520 nm to relative light units at 495 nm. For analysis, data from multiple runs were averaged and each compound was tested over 2 to 20 runs. Each run included two plates, and replicates were included in each plate. The data obtained for each plate was averaged and the data was imported into 3DX. Data from multiple runs were summed as the mean of replicates for ratio calculations to calculate _Ki and _IC50 values. Letters ND and/or no data in any box of Tables 5 and 6 indicate that no _Ki or _IC50 values were determined.

Human Whole Blood Assay

In vitro cellular assays were performed using human whole blood collected in heparin-containing tubes to test the ability of compounds to modulate the leukotriene pathway in human whole blood. Blood was diluted 1:1 in RPMI medium, pre-incubated with different concentrations of test compounds for 15 minutes at 37°C, and then stimulated with calcium ionophore A23187 (7 μg/mL) for 30 minutes at 37°C. The samples were then centrifuged and the plasma removed. Plasma was diluted with assay buffer and LTB ₄ concentrations were measured using a commercial kit (EnzoLifeSciences). The concentration of each compound required to inhibit (modulate) the recombinase activity ( _IC50 ) to a half-maximal effect was calculated by a four-parameter equation using the program GraphPad Prism (GraphPad software).

Table 5 FLAP binding and human whole blood assay data

The following compounds were tested in further runs of the above assay and the data are presented in Table 6.

Table 6 FLAP binding and human whole blood assay data

Throughout this application, various publications are referenced. The disclosures of these publications are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.

While the foregoing description teaches the principles of the invention and the examples are provided by way of illustration, it should be understood that the practice of the invention encompasses all conventional modifications, changes and changes that come within the scope of the appended claims and their equivalents. form and/or modified form.

Claims (16)

1. the compound of formula (I) or its pharmacy acceptable salt,

(I)

Wherein

L is key ,-CH ₂-,-CH ₂cH ₂-,-CH ₂cH ₂cH ₂-,-CH ₂cH ₂nH-,-CH ₂c (=O) NH-, – CH ₂c (OH) (H) CH ₂– Huo – CH ₂c (OH) (H) CH ₂nH –;

R ₁for halogeno-group, C _1-5alkyl, C _3-6cycloalkyl or cyclohexyl methyl;

R ₂for H, C _1-4alkyl, hydroxyl, amino, cyano group, – CH ₂c (=O) O-(tertiary butyl), – CH ₂c (=O) O-(ethyl), – CH ₂c (=O) OH, – NHS (=O) ₂cH ₃, the tertiary butyl (dimethyl) silyl-oxygen base ,-NHCH ₃,-N (CH ₃) ₂,-NH-(sec.-propyl), the phenyl be optionally substituted, 5 yuan that are optionally substituted or 6 yuan of heteroaryls, C _3-6cycloalkyl or the heterocyclic radical be optionally substituted;

Wherein said 5 yuan or 6 yuan of heteroaryls, described heterocyclic radical or described phenyl be optionally and be selected from following substituting group by 1-4 independently and replace:

C _1-4alkyl, – CH ₂-methoxyl group, – C (=O) OH, – CH ₂c (=O) OH, – C (=O)-O-CH ₂cH ₃, – C (=O)-O-CH ₃, – C (=O)-O-(tertiary butyl), – NH ₂, – N (CH ₃) ₂, – NH-(isobutyl-), – NH (CH ₂) ₂nHC (=O)-O-tertiary butyl, – NH (CH ₂) ₂nH ₂, – NH (CH ₂) ₂n (CH ₃) ₂, – C (=O) NH ₂, – C (=O) CH ₃, oxo base, halogeno-group, hydroxyl, methoxyl group, trifluoromethyl, trifluoromethoxy, methoxymethyl, – S (=O) ₂cH ₃, – S (=O) ₂nH ₂, – S (=O) ₂nH (CH ₃), – S (=O) ₂n (CH ₃) ₂, – S-CH ₃, cyano group, 1H-TETRAZOLE-5-base, thiophene-2-base, cyclopropyl, azetidine-1-base, phenyl, 4 '-(trifluoromethyl) phenyl, benzyl, 1,5-dioxa-9-azaspiro [5.5] undecane-9-base, 5-pyrimidine-2-amine and five fluoro-λ ~ 6 ~-sulfanyl;

Ring A is selected from:

, , , , , , , , , with ;

R ₃for H, cyano group, methyl, methoxyl group, halogeno-group Huo – NH ₂;

R ₄for H or methyl; And

R ₅for H, cyano group, halogeno-group, CF ₃huo – NH ₂.

2. compound according to claim 1 or its pharmacy acceptable salt, wherein

L is Jian Huo – CH ₂–;

R ₁for the tertiary butyl or cyclobutyl;

R ₂for the phenyl be optionally substituted or the 6 yuan of heteroaryls be optionally substituted;

The replacement of wherein said phenyl or described 6 yuan of heteroaryls is selected from:

Hydroxyl, fluoro base, methoxyl group, cyano group, amino ,-C (=O)-NH ₂with five fluoro-λ ~ 6 ~-sulfanyl;

Ring A is

or ; And

R ₃for H or cyano group.

3. compound according to claim 2 or its pharmacy acceptable salt, wherein

L is Jian Huo – CH ₂–;

R ₁for the tertiary butyl or cyclobutyl;

R ₂for the phenyl be optionally substituted, the pyridine be optionally substituted or the pyrimidine that is optionally substituted;

The replacement of wherein said phenyl, described pyridine or described pyrimidine is selected from:

Hydroxyl, fluoro base, methoxyl group, cyano group, amino ,-C (=O)-NH ₂with five fluoro-λ ~ 6 ~-sulfanyl; And

Ring A is

or .

4. compound according to claim 1, wherein said compound is selected from:

5-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-) pyrazine-2-amine,

3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenol,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(trifluoromethyl) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[3-(trifluoromethyl) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[2-(trifluoromethyl) benzyl] oxygen base } phenyl) pyrazine-2-amine,

3-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } phenylformic acid,

4-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } phenylformic acid,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[3-(methylsulfanyl) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(methylsulfanyl) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[2-(trifluoromethoxy) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[3-(trifluoromethoxy) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(trifluoromethoxy) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-(3-{ [the chloro-2-of 4-(methylsulfanyl) benzyl] oxygen base }-4-cyclobutyl-2-fluorophenyl) pyrazine-2-amine,

1-(4-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-methyl } phenyl)-ethyl ketone,

5-[the fluoro-3-of 4-cyclobutyl-2-(pyridin-3-yl methoxyl group) phenyl] pyrazine-2-amine,

5-[the fluoro-3-of 4-cyclobutyl-2-(pyridin-4-yl methoxyl group) phenyl] pyrazine-2-amine,

4-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } cyanobenzene,

3-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } cyanobenzene,

3-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } benzamide,

2-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } cyanobenzene,

2-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } benzamide,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(1H-TETRAZOLE-5-base) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[3-(1H-TETRAZOLE-5-base) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[2-(1H-TETRAZOLE-5-base) benzyl] oxygen base } phenyl) pyrazine-2-amine,

(4-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } phenyl) acetic acid,

5-[the fluoro-3-of 4-cyclobutyl-2-(pyridine-2-ylmethoxy) phenyl] pyrazine-2-amine,

4-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl }-N, N-Dimethyl-benzenesulfonamide,

4-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-methyl }-benzsulfamide,

4-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl }-N-methyl benzenesulfonamide,

The fluoro-3-of 5-{4-cyclobutyl-2-[(4-luorobenzyl) oxygen base] phenyl } pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(3-luorobenzyl) oxygen base] phenyl } pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(2-luorobenzyl) oxygen base] phenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[(2,6-difluorobenzyl) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[(2,3-difluorobenzyl) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[(3,4-difluorobenzyl) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

5-{3-[(2-chlorobenzyl) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-{3-[(3-chlorobenzyl) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-{3-[(4-chlorobenzyl) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[(2,6-dichloro benzyl) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[(2,5-dichloro benzyl) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[(2,3-dichloro benzyl) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[(2,4-dichloro benzyl) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[(3,4-dimethyl benzyl) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

5-(3-{ [the chloro-3-of 2-(trifluoromethyl) benzyl] oxygen base }-4-cyclobutyl-2-fluorophenyl) pyrazine-2-amine,

5-(3-{ [the chloro-2-of 5-(trifluoromethyl) benzyl] oxygen base }-4-cyclobutyl-2-fluorophenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[the fluoro-2-of 4-(trifluoromethyl) benzyl] oxygen base } phenyl) pyrazine-2-amine,

5-{3-[(the chloro-5-luorobenzyl of 2-) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

2-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } phenylformic acid,

The fluoro-3-of 5-{4-cyclobutyl-2-[(1-methyl isophthalic acid H-pyrazole-3-yl) methoxyl group] phenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[(3-cyclopropyl-1,2,4- diazole-5-base) methoxyl group]-2-fluorophenyl } pyrazine-2-amine,

[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] tert.-butyl acetate,

[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] acetic acid,

Racemize 1-(3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl) pyridine-2 (1H)-one,

Racemize 3-(3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl) pyrimidine-4 (3H)-one,

Racemize 2-(3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl) pyridazine-3 (2H)-one,

Racemize 1-(3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl) pyrazine-2 (1H)-one,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidine-5-base is amino) propan-2-ol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrimidine-2--amino) propan-2-ol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-(pyrazine-2-base is amino) propan-2-ol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-((5-aminopyrimidine-2-base) is amino) propan-2-ol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-((6-aminopyrimidine-4-base) is amino) propan-2-ol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-pyrazol-1-yl) propan-2-ol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-imidazoles-1-base) propan-2-ol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,4-triazol-1-yl) propan-2-ol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-(1H-1,2,3-triazol-1-yl) propan-2-ol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-(2H-1,2,3-triazole-2-base) propan-2-ol,

Racemize 5-amino-1-(3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)-1H-pyrazoles-4-formonitrile HCN,

Racemize 1-(5-amino-1H-1,2,3-triazol-1-yl)-3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) propan-2-ol,

Racemize 1-((1H-pyrazoles-5-base) is amino)-3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) propan-2-ol,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[1-(methylsulfanyl) piperidin-4-yl] methoxyl group }-phenyl)-pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(4-methylpyrimidine-2-base)-oxygen base]-phenyl } pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(5-methyl isophthalic acid, 2,4- diazole-3-base) methoxyl group] phenyl } pyrazine-2-amine,

5-[4-cyclobutyl-3-(cyclohexyl methoxy)-2-fluorophenyl] pyrazine-2-amine,

5-[4-cyclobutyl-3-(cyclo propyl methoxy)-2-fluorophenyl] pyrazine-2-amine,

5-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } furans-2-carboxylic acid, ethyl ester,

4-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-methyl }-piperidines-1-carboxylic acid tert-butyl ester,

The fluoro-3-of 5-{4-cyclobutyl-2-[(3-methyl isophthalic acid, 2,4- diazole-5-base)-methoxyl group]-phenyl }-pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[2-methoxyl group-5-(five fluoro-λ ~ 6 ~-sulfanyl)-benzyl]-oxygen base }-phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[the fluoro-5-of 2-(five fluoro-λ ~ 6 ~-sulfanyl) benzyl]-oxygen base }-phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[the fluoro-4-of 2-(five fluoro-λ ~ 6 ~-sulfanyl) benzyl]-oxygen base }-phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(five fluoro-λ ~ 6 ~-sulfanyl) benzyl]-oxygen base }-phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[3-(five fluoro-λ ~ 6 ~-sulfanyl) benzyl]-oxygen base }-phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[2-(five fluoro-λ ~ 6 ~-sulfanyl) benzyl]-oxygen base }-phenyl)-pyrazine-2-amine,

5-[4-cyclobutyl-3-(cyclobutyl methoxyl group)-2-fluorophenyl] pyrazine-2-amine,

5-[3-(benzyl oxygen base)-4-cyclobutyl-2-fluorophenyl] pyrazine-2-amine,

4-{2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] ethyl } phenylformic acid,

5-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } furans-2-carboxylic acid,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidine-4-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(4-phenyl pyrimidine-2-base) oxygen base] phenyl } pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(methylsulfanyl) pyrimidine-2-base] oxygen base } phenyl) pyrazine-2-amine,

5-{4-cyclobutyl-3-[(4,6-dimethyl pyrimidine-2-base) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(1-methylethyl) pyrimidine-2-base] oxygen base } phenyl) pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(4-thiophene-2-yl pyrimidines-2-base) oxygen base] phenyl } pyrazine-2-amine,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-formonitrile HCN,

The fluoro-3-of 5-{4-cyclobutyl-2-[(4-methoxy pyrimidine-2-base) oxygen base] phenyl } pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(5-methoxy pyrimidine-2-base) oxygen base] phenyl } pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(methylsulfanyl) pyrimidine-2-base] oxygen base } phenyl) pyrazine-2-amine,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-6-methylpyrimidine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(6-methoxy pyrimidine-4-base) oxygen base] phenyl } pyrazine-2-amine,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-alcohol,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-6-methoxy pyrimidine-2-amine,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-2-methoxy pyrimidine-4-amine,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] cyanobenzene,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[6-(trifluoromethyl) pyridine-2-base] oxygen base } phenyl) pyrazine-2-amine,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl benzoate,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[5-(trifluoromethyl) pyrimidine-2-base] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[5-(trifluoromethyl) pyrazine-2-base] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[6-(trifluoromethyl) pyridazine-3-base] oxygen base } phenyl) pyrazine-2-amine,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridine-3-carboxylic acid methyl esters,

5-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridine-2-formonitrile HCN,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridine-2-formonitrile HCN,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridine-3-formonitrile HCN,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridine-2-formonitrile HCN,

3-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridine-2-formonitrile HCN,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[5-(trifluoromethyl) pyridine-2-base] oxygen base } phenyl) pyrazine-2-amine,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridine-3-formonitrile HCN,

The fluoro-3-of 5-{4-cyclobutyl-2-[4-(five fluoro-λ ~ 6 ~-sulfanyl) phenoxy group]-phenyl }-pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[4-(methylsulfanyl) phenoxy group] phenyl } pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[2-(methylsulfanyl) phenoxy group] phenyl } pyrazine-2-amine,

5-[the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl] pyrazine-2-amine,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-amine,

5-{3-[two (trifluoromethyl) phenoxy group of 3,4-]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[3-(trifluoromethyl) pyridine-2-base] oxygen base } phenyl) pyrazine-2-amine,

5-{3-[(3-chloropyridine-2-base) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-{3-[the chloro-4-of 2-(methylsulfanyl) phenoxy group]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[2-(trifluoromethyl) pyrimidine-4-yl] oxygen base } phenyl) pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[6-(trifluoromethyl) pyrimidine-4-yl] oxygen base } phenyl) pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[3-methyl-4-(methylsulfanyl) phenoxy group] phenyl } pyrazine-2-amine,

5-(the fluoro-3-of 4-cyclobutyl-2-(4-(methylsulfanyl)-2-(trifluoromethyl) phenoxy group)-phenyl)-pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[6-(trifluoromethyl) pyridin-3-yl] oxygen base } phenyl) pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(3-Methoxy Pyridine-2-base) oxygen base] phenyl } pyrazine-2-amine,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(trifluoromethyl) pyrimidine-2-base] oxygen base } phenyl) pyrazine-2-amine,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-5-(methylsulfanyl)-cyanobenzene,

The fluoro-3-of 5-{4-cyclobutyl-2-[4-(methylsulfanyl)-3-(trifluoromethyl)-phenoxy group]-phenyl }-pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(2-methylpyrimidine-4-base) oxygen base] phenyl } pyrazine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[2-(1-methylethyl) pyrimidine-4-yl] oxygen base } phenyl) pyrazine-2-amine,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-amine,

5-{3-[(2-chloropyrimide-4-base) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-{3-[(6-azetidine-1-yl pyrimidines-4-base) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine trifluoroacetate,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-N, N-dimethyl-2-(trifluoromethyl) pyrimidine-4-amine,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-2-methylpyrimidine-4-amine trifluoroacetate,

5-{4-cyclobutyl-3-[(6-cyclopropyl-pyrimidine-4-base) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl) pyrimidine-2-amine,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-6-chloropyrimide-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(2-phenyl pyrimidine-4-base) oxygen base] phenyl } pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(6-phenyl pyrimidine-4-base) oxygen base] phenyl } pyrazine-2-amine,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-2-benzyl pyrimidines-4-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[6-(1-methylethyl) pyrimidine-4-yl] oxygen base } phenyl) pyrazine-2-amine,

3-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-1-methyl-5-(trifluoromethyl)-1H-pyrazoles-4-formonitrile HCN,

[2-({ 2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-yl } is amino) ethyl] t-butyl carbamate,

N-{4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-2-base } ethane-1,2-diamines,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-carboxylate methyl ester trifluoroacetate,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-carboxylic acid,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] phenylformic acid,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridine-3-carboxylic acid,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] benzamide,

N'-{4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-2-base }-N, N-dimethyl ethane-1,2-diamine salts acidulants,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-methane amide,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-5-amine,

5-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-) pyrimidine-2-amine,

3-(2-aminopyrimidine-5-base)-6-cyclobutyl-2-fluorophenol,

5-[the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl] pyrimidine-2-amine,

5-{3-[(4-aminopyrimidine-2-base) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrimidine-2-amine,

4-[3-(2-aminopyrimidine-5-base)-6-cyclobutyl-2-fluorophenoxy]-6-(methoxymethyl) pyrimidine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(4-methylpyrimidine-2-base) oxygen base] phenyl } pyrimidine-2-amine,

5-{3-[(6-aminopyrimidine-4-base) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrimidine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(1-methylethyl) pyrimidine-2-base] oxygen base } phenyl) pyrimidine-2-amine,

4-[3-(2-aminopyrimidine-5-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-2-amine,

5-{4-cyclobutyl-3-[(4,6-dimethyl pyrimidine-2-base) oxygen base]-2-fluorophenyl } pyrimidine-2-amine,

4-(3-(2-aminopyrimidine-5-base)-6-cyclobutyl-2-fluorophenoxy)-6-isopropylpyrimidin-2-amine,

2-[3-(2-aminopyrimidine-5-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-methane amide,

5-(the fluoro-3-of 4-cyclobutyl-2-((6-methoxy pyrimidine-4-base) oxygen base) phenyl) pyrimidine-2-amine trifluoroacetate,

6-[3-(2-aminopyrimidine-5-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-alcohol trifluoroacetate,

6-amino-3-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-) pyrazine-2-formonitrile HCN,

6-amino-3-(the fluoro-3-hydroxyphenyl of 4-cyclobutyl-2-) pyrazine-2-formonitrile HCN,

3-{ [3-(5-Amino 3 cyano pyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } phenylformic acid,

2-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-)-5H-pyrrolo-[2,3-b] pyrazine,

The fluoro-3-of 6-cyclobutyl-2-(5H-pyrrolo-[2,3-b] pyrazine-2-base) phenol,

2-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(trifluoromethyl) benzyl] oxygen base } phenyl)-5H-pyrrolo-[2,3-b] pyrazine trifluoroacetate,

2-[3-(benzyl oxygen base)-4-cyclobutyl-2-fluorophenyl]-5H-pyrrolo-[2,3-b] pyrazine,

5-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-) pyridine-2-amine hydrochlorate,

5-(the fluoro-3-hydroxyphenyl of 4-cyclobutyl-2-) pyridine-2-amine,

5-methyl-4-((3-(6-aminopyridine-3-base)-6-cyclobutyl-2-fluorophenoxy) methyl) benzoic ether,

4-((3-(6-aminopyridine-3-base)-6-cyclobutyl-2-fluorophenoxy) methyl) phenylformic acid,

5-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-)-1H-imidazo [4,5-b] pyrazine,

6-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-)-3H-imidazo [4,5-b] pyridine,

7-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-)-3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitraes] piperazine,

6-cyclobutyl-3-(3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitrae] piperazine-7-base)-2-fluorophenol,

7-[3-(benzyl oxygen base)-4-cyclobutyl-2-fluorophenyl]-3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitraes] piperazine,

3-{ [6-cyclobutyl-3-(3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitrae] piperazine-7-base)-2-fluorophenoxy] methyl } cyanobenzene,

7-(the fluoro-3-{ of 4-cyclobutyl-2-[3-(methylsulfanyl) benzyl] oxygen base } phenyl)-3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitraes] piperazine,

7-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(methylsulfanyl) benzyl] oxygen base } phenyl)-3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitraes] piperazine,

4-{ [6-cyclobutyl-3-(3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitrae] piperazine-7-base)-2-fluorophenoxy] methyl } cyanobenzene,

7-(the fluoro-3-{ of 4-cyclobutyl-2-[4-(trifluoromethyl) benzyl] oxygen base } phenyl)-3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitraes] piperazine,

3-{ [6-cyclobutyl-3-(3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitrae] piperazine-7-base)-2-fluorophenoxy] methyl } benzamide,

4-{ [6-cyclobutyl-3-(3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitrae] piperazine-7-base)-2-fluorophenoxy] methyl } benzamide,

7-(the fluoro-3-{ of 4-cyclobutyl-2-[6-(trifluoromethyl) pyridine-2-base] oxygen base } phenyl)-3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitraes] piperazine,

(4-{ [6-cyclobutyl-3-(3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitrae] piperazine-7-base)-2-fluorophenoxy] methyl } phenyl) acetic acid,

4-{ [6-cyclobutyl-3-(3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitrae] piperazine-7-base)-2-fluorophenoxy] methyl } phenylformic acid,

3-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-)-7H-pyrrolo-[2,3-c] pyridazine,

5-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-)-2,3-dihydro-1H-pyrrolo-[2,3-b] pyridines,

6-cyclobutyl-3-(2,3-dihydro-1H-pyrrolo-[2,3-b] pyridine-5-base)-2-fluorophenol,

3-(5-Aminopyrazine-2-the base)-6-tertiary butyl-2-fluorophenol,

5-(the 4-tertiary butyl-3-{ [tertiary butyl (dimethyl) silyl] oxygen base }-2-fluorophenyl) pyrazine-2-amine,

5-[the fluoro-3-of the 4-tertiary butyl-2-(pyrimidine-2-yloxy) phenyl] pyrazine-2-amine,

6-[3-(5-Aminopyrazine-2-the base)-6-tertiary butyl-2-fluorophenoxy] pyrimidine-4-amine,

2-[3-(5-Aminopyrazine-2-the base)-6-tertiary butyl-2-fluorophenoxy] pyrimidine-4-amine,

The fluoro-3-of the 5-{4-tertiary butyl-2-[(6-methoxy pyrimidine-4-base) oxygen base] phenyl } pyrazine-2-amine,

5-(the fluoro-3-p-methoxy-phenyl of the 4-tertiary butyl-2-) pyrazine-2-amine,

3-(2-aminopyrimidine-5-the base)-6-tertiary butyl-2-fluorophenol,

5-(the 4-tertiary butyl-3-{ [tertiary butyl (dimethyl) silyl] oxygen base }-2-fluorophenyl) pyrimidine-2-amine,

5-[the fluoro-3-of the 4-tertiary butyl-2-(pyrimidine-2-yloxy) phenyl] pyrimidine-2-amine,

5-{3-[(6-aminopyrimidine-4-base) oxygen the base]-4-tertiary butyl-2-fluorophenyl } pyrimidine-2-amine,

5-{3-[(4-aminopyrimidine-2-base) oxygen the base]-4-tertiary butyl-2-fluorophenyl } pyrimidine-2-amine,

5-(the fluoro-3-p-methoxy-phenyl of the bromo-2-of 4-) pyrazine-2-amine,

5-(the fluoro-3-p-methoxy-phenyl of 4-cyclopentyl-2-) pyrazine-2-amine,

5-[3-(benzyl oxygen base)-4-cyclopentyl-2-fluorophenyl] pyrazine-2-amine,

5-[the fluoro-3-of 4-cyclopentyl-2-(1-methyl ethoxy) phenyl] pyrazine-2-amine,

2-[3-(benzyl oxygen base)-4-cyclopentyl-2-fluorophenyl]-5H-pyrrolo-[2,3-b] pyrazine,

5-[3-(benzyl oxygen base)-4-tert-butyl-phenyl] pyrazine-2-amine,

5-[the chloro-2-fluorophenyl of 3-(benzyl oxygen base)-4-] pyrazine-2-amine,

5-[3-(benzyl oxygen base)-4-cyclobutylphenyl] pyrazine-2-amine,

3-amino-6-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-) pyrazine-2-formonitrile HCN,

6-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-) pyridazine-3-amine,

The fluoro-3-of 6-cyclobutyl-2-(1H-pyrrolo-[2,3-b] pyridine-5-base) phenol,

The fluoro-3-of 6-cyclobutyl-2-(7H-pyrrolo-[2,3-c] pyridazine-3-base) phenol,

3-amino-6-(the fluoro-3-hydroxyphenyl of 4-cyclobutyl-2-) pyrazine-2-formonitrile HCN,

3-(6-amino pyridazine-3-base)-6-cyclobutyl-2-fluorophenol,

5,5'-((pyrimidine-2,4-bis-base two (oxygen base)) two (fluoro-3, the 1-phenylenes of 4-cyclobutyl-2-)) two (pyrazine-2-amine),

7-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl)-3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitrae] piperazine,

2-(6-cyclobutyl-3-(3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitrae] piperazine-7-base)-2-fluorophenoxy) pyrimidine-4-amine,

7-(the fluoro-3-of 4-cyclobutyl-2-((6-methoxy pyrimidine-4-base) oxygen base) phenyl)-3,4-dihydro-2H-pyrido [3,2-b] [Isosorbide-5-Nitraes] piperazine,

5-(the fluoro-3-of 4-cyclobutyl-2-((6-methoxy pyrimidine-4-base) oxygen base) phenyl)-1H-pyrrolo-[2,3-b] pyridine,

2-(the fluoro-3-of 4-cyclobutyl-2-((6-methoxy pyrimidine-4-base) oxygen base) phenyl)-5H-pyrrolo-[2,3-b] pyrazine,

2-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl)-5H-pyrrolo-[2,3-b] pyrazine,

6-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl) pyridazine-3-amine,

6-(the fluoro-3-of 4-cyclobutyl-2-((6-methoxy pyrimidine-4-base) oxygen base) phenyl) pyridazine-3-amine,

6-(3-(6-amino pyridazine-3-base)-6-cyclobutyl-2-fluorophenoxy) pyrimidine-4-alcohol,

4-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) pyrimidine-2-formonitrile HCN,

6-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-N, N, 2-trimethylpyrimidine-4-amine,

4-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-N, N, 6-trimethylpyrimidine-2-amine,

6-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-N, N-dimethyl pyrimidine-4-amine,

5-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester,

5-(the fluoro-3-of 4-cyclobutyl-2-((5-(methylsulfanyl) pyridine-2-base) oxygen base) phenyl) pyrazine-2-amine,

4-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-6-(tertiary butyl) pyrimidine-2-amine,

5-(3-((4-(1,5-dioxa-9-azaspiro [5.5] undecane-9-base) pyrimidine-2-base) oxygen base)-4-cyclobutyl-2-fluorophenyl) pyrazine-2-amine,

4-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-6-isobutyl-pyrimidine-2-amine,

5-(the fluoro-3-p-methoxy-phenyl of 4-cyclobutyl-2-)-1H-pyrrolo-[2,3-b] pyridine,

N-(2-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-ethyl)-methane-sulfonamide,

5-(the fluoro-3-of 4-cyclobutyl-2-(2-morpholine oxyethyl group) phenyl) pyrazine-2-amine,

4-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) ethyl butyrate,

3-((3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) methyl)-azetidine-1-carboxylic acid tert-butyl ester,

3-((3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) methyl)-tetramethyleneimine-1-carboxylic acid tert-butyl ester,

2-((3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) methyl)-tetramethyleneimine-1-carboxylic acid tert-butyl ester,

3-((3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-methyl)-piperidines-1-carboxylic acid tert-butyl ester,

2-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) ethanol,

4-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) butyric acid,

5-(the fluoro-3-of 4-cyclobutyl-2-((tetrahydrofuran (THF)-2-base) methoxyl group) phenyl) pyrazine-2-amine,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-(isobutylamino)-propyl-2-alcohol,

Racemize 3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) propane-1,2-glycol,

Racemize 1-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-3-morpholine propan-2-ol,

Racemize 4-(3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-2-hydroxypropyl)-thiomorpholine 1,1-dioxide,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyridazine-4-base oxygen base) phenyl) pyrazine-2-amine,

3-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) pyrazine-2-amine,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrazine-2-base oxygen base) phenyl) pyrazine-2-amine,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-4-yl oxygen base) phenyl) pyrazine-2-amine,

4-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy)-N-isobutyl-pyrimidine-2-amine trifluoroacetate,

2-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl }-1,3-benzo azoles-5-carboxylate methyl ester,

3-({ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] ethanoyl } is amino)-4-HBA methyl esters,

5-[the fluoro-3-of 4-cyclobutyl-2-(tetrahydrochysene-2H-pyrans-4-ylmethoxy) phenyl] pyrazine-2-amine,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-3-(methylsulfanyl) cyanobenzene,

5-{3-[two (trifluoromethyl) phenoxy group of 2,4-]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[3-(dimethylamino) propoxy-]-2-fluorophenyl } pyrazine-2-amine,

5-{4-cyclobutyl-3-[2-(dimethylamino) oxyethyl group]-2-fluorophenyl } pyrazine-2-amine,

4-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-N, 6-dimethyl pyrimidine-2-amine,

2-[the fluoro-3-(7 of 6-cyclobutyl-2- h-pyrrolo-[2,3- c] pyridazine-3-base) phenoxy group] pyrimidine-4-amine,

5-{4-cyclobutyl-3-[(6,7-Difluoroquinoxalin-2-base) oxygen base]-2-fluorophenyl } pyrazine-2-amine,

2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] quinazoline-4-amine,

2-amino-5-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyrimidine-4-formonitrile HCN,

2-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl }-1,3-benzo azoles-5-carboxylate methyl ester,

3-({ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] ethanoyl } is amino)-4-HBA methyl esters,

[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] acetonitrile,

5-[the fluoro-3-of 4-cyclobutyl-2-(pyridazine-3-base oxygen base) phenyl] pyrazine-2-amine,

5-[the fluoro-3-of 4-cyclopropyl-2-(pyrimidine-2-yloxy) phenyl] pyrazine-2-amine,

2-[3-(5-Aminopyrazine-2-base)-6-cyclopropyl-2-fluorophenoxy] pyrimidine-4-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[(1-methyl isophthalic acid h-imidazoles-2-base) methoxyl group] phenyl } pyrazine-2-amine trifluoroacetate,

2-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl }-1,3- azoles-4-carboxylate methyl ester trifluoroacetate,

2-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl }-1,3- azoles-4-carboxylic acid trifluoroacetate,

5-[3-(1,3-benzothiazole-2-ylmethoxy)-4-cyclobutyl-2-fluorophenyl] pyrazine-2-amine trifluoroacetate,

The fluoro-3-of 5-{4-cyclobutyl-2-[(1-methyl isophthalic acid h-imidazol-4 yl) methoxyl group] phenyl } pyrazine-2-amine trifluoroacetate,

The fluoro-3-of 5-{4-cyclobutyl-2-[(1-methyl isophthalic acid h-imidazoles-5-base) methoxyl group] phenyl } pyrazine-2-amine trifluoroacetate,

2-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } pyridine-3-formonitrile HCN trifluoroacetate,

The fluoro-3-of 5-{4-cyclobutyl-2-[(2-methyl isophthalic acid, 3-thiazole-4-yl) methoxyl group] phenyl } pyrazine-2-amine trifluoroacetate,

5-[the fluoro-3-of 4-cyclobutyl-2-(pyridazine-3-ylmethoxy) phenyl] pyrazine-2-amine trifluoroacetate,

5-{3-[(5-chloropyridine-2-base) methoxyl group]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine trifluoroacetate,

5-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } pyridine-2-formonitrile HCN trifluoroacetate,

[(5-methyl is different for the fluoro-3-of 5-{4-cyclobutyl-2- azoles-3-base) methoxyl group] phenyl } pyrazine-2-amine trifluoroacetate,

6-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } pyridine-2-formonitrile HCN trifluoroacetate,

2-{2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] ethyl }-1 h-isoindole-1,3 (2 h)-diketone,

5-[3-(2-amino ethoxy)-4-cyclobutyl-2-fluorophenyl] pyrazine-2-amine,

The fluoro-3-of 5-{4-cyclobutyl-2-[2-(pyrazine-2-base is amino) oxyethyl group] phenyl } pyrazine-2-amine trifluoroacetate,

n-{ 2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] ethyl } pyrimidine-2-amine trifluoroacetate,

n-{ 2-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] ethyl } pyrimidine-4-amine,

5-[the fluoro-3-of 4-cyclobutyl-2-(piperidin-4-yl methoxyl group) phenyl] pyrazine-2-amine hydrochlorate,

Racemize 5-[the fluoro-3-of 4-cyclobutyl-2-(piperidines-3-ylmethoxy) phenyl] pyrazine-2-amine,

Racemize 5-[the fluoro-3-of 4-cyclobutyl-2-(pyrrolidin-3-yl methoxyl group) phenyl] pyrazine-2-amine,

5-[3-(azetidine-3-ylmethoxy)-4-cyclobutyl-2-fluorophenyl] pyrazine-2-amine,

Racemize 5-[the fluoro-3-of 4-cyclobutyl-2-(pyrrolidin-2-yl methoxyl group) phenyl] pyrazine-2-amine,

Racemize 51-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-3-piperidin-1-yl propan-2-ol,

Racemize 1-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-3-(methylamino) propan-2-ol,

Racemize 1-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-3-[(1-methylethyl) is amino] propan-2-ol,

Racemize 1-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-3-pyrrolidin-1-yl propan-2-ol,

Racemize 1-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-3-(dimethylamino) propan-2-ol,

Mixture of diastereomers 1-{3-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl } tetramethyleneimine-3-alcohol,

Racemize 1-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-3-piperazine-1-base propan-2-ol,

Racemize 1-{3-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl } pyrimidine-2 (1H)-one,

Racemize 1-{3-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl }-1,3-dihydro-2 h-2-ketone benzimidaozole,

Racemize 1-{3-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-2-hydroxypropyl } tetrahydroglyoxaline-2-ketone,

2'-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy]-5,5'-bis-pyrimidine-2-amine,

5-[the fluoro-4-methyl of 2--3-(pyrimidine-2-yloxy) phenyl] pyrazine-2-amine,

2-[3-(5-Aminopyrazine-2-base) the fluoro-6-methylphenoxy of-2-] pyrimidine-4-amine,

5-[the fluoro-3-of 4-ethyl-2-(pyrimidine-2-yloxy) phenyl] pyrazine-2-amine,

2-[3-(5-Aminopyrazine-2-base)-6-ethyl-2-fluorophenoxy] pyrimidine-4-amine,

5-[the fluoro-4-of 2-(1-methylethyl)-3-(pyrimidine-2-yloxy) phenyl] pyrazine-2-amine,

5-[the fluoro-4-propyl group of 2--3-(pyrimidine-2-yloxy) phenyl] pyrazine-2-amine,

5-(the fluoro-3-of 4-cyclohexyl-2-(pyrimidine-2-yloxy) phenyl) pyrazine-2-amine,

5-(4-(cyclohexyl methyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl) pyrazine-2-amine,

5-(the fluoro-4-isopentyl of 2--3-(pyrimidine-2-yloxy) phenyl) pyrazine-2-amine,

5-(the fluoro-4-isobutyl-of 2--3-(pyrimidine-2-yloxy) phenyl) pyrazine-2-amine,

5-(the fluoro-4-neo-pentyl of 2--3-(pyrimidine-2-yloxy) phenyl) pyrazine-2-amine,

2-(3-(5-Aminopyrazine-2-base)-6-cyclohexyl-2-fluorophenoxy) pyrimidine-4-amine,

2-(3-(5-Aminopyrazine-2-base)-6-(cyclohexyl methyl)-2-fluorophenoxy) pyrimidine-4-amine,

2-(3-(5-Aminopyrazine-2-base)-2-fluoro-6-isopentyl phenoxy group) pyrimidine-4-amine,

2-(3-(5-Aminopyrazine-2-base)-2-fluoro-6-isobutyl-phenoxy group) pyrimidine-4-amine,

5-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) pyrimidine-2-methane amide,

((thiazole is [4,5-also for the fluoro-3-of 4-cyclobutyl-2-for 5- b] pyridine-2-base oxygen base) phenyl) pyrazine-2-amine,

5-(the fluoro-3-of 4-cyclobutyl-2-((5-thiotolene also [2,3- d] pyrimidine-4-yl) oxygen base) phenyl) pyrazine-2-amine,

n ⁴ -(2-(3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy) ethyl) pyrimidine-2,4-diamines,

5-(the fluoro-4-of 2-(penta-3-base)-3-(pyrimidine-2-yloxy) phenyl) pyrazine-2-amine,

5-(the fluoro-4-methyl of 2--3-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-3-of 4-ethyl-2-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-4-propyl group of 2--3-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-4-sec.-propyl of 2--3-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-3-of 4-cyclopropyl-2-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-4-isobutyl-of 2--3-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-4-neo-pentyl of 2--3-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-4-of 2-(penta-3-base)-3-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-3-of 4-cyclohexyl-2-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(4-(cyclohexyl methyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-4-isopentyl of 2--3-(pyrimidine-2-yloxy) phenyl) pyrimidine-2-amine,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl)-4-methylpyrimidine-2-amine,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl)-4-methylpyrimidine-2-amine,

The chloro-5-of 3-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl) pyridine-2-amine,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl)-3-chloropyridine-2-amine,

2-amino-5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl) nicotinic acid nitrile,

2-amino-5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl) nicotinic acid nitrile,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl)-3-fluorine pyridine-2-amine,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl)-3-fluorine pyridine-2-amine,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl)-3-(trifluoromethyl) pyridine-2-amine,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl)-3-(trifluoromethyl) pyridine-2-amine,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl) pyridine-2,3-diamines,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl) pyridine-2,3-diamines,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl)-3-methylpyrazine-2-amine,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl)-3-methylpyrazine-2-amine,

The chloro-5-of 3-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl) pyrazine-2-amine,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl)-3-chloropyrazine-2-amine,

3-amino-6-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl) pyrazine-2-formonitrile HCN,

3-amino-6-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl) pyrazine-2-formonitrile HCN,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl)-3-Calmazine-2-amine,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl)-3-Calmazine-2-amine,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl)-3-methoxypyrazine-2-amine,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl)-3-methoxypyrazine-2-amine,

5-(the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-yloxy) phenyl) pyrazine-2,3-diamines,

5-(4-(tertiary butyl)-2-fluoro-3-(pyrimidine-2-yloxy) phenyl) pyrazine-2,3-diamines,

3-(5-Aminopyrazine-2-base)-6-ethyl-2-fluorophenol,

5-[the fluoro-3-of the 4-tertiary butyl-2-(pyrimidine-2-yloxy) phenyl]-1H-pyrrolo-[2,3-b] pyridine,

5-{3-[(PA-4-base) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-{3-[(6-Aminopyrazine-2-base) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-[the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-5-base oxygen base) phenyl] pyrazine-2-amine,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridazine-4-amine,

3-(5-Aminopyrazine-2-base)-6-cyclohexyl-2-fluorophenol,

3-(5-Aminopyrazine-2-base)-6-(cyclohexyl methyl)-2-fluorophenol,

5-[the fluoro-3-of 4-cyclopentyl-2-(pyrimidine-2-yloxy) phenyl] pyrimidine-2-amine,

5-[the fluoro-3-of 4-cyclopentyl-2-(pyrimidine-2-yloxy) phenyl] pyrazine-2-amine,

2-[3-(5-Aminopyrazine-2-base)-6-cyclopentyl-2-fluorophenoxy] pyrimidine-4-amine,

5-{3-[(4-aminopyrimidine-2-base) oxygen base]-4-cyclopentyl-2-fluorophenyl } pyrimidine-2-amine,

6-[3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] pyridazine-3-amine,

5-[the fluoro-3-of 4-cyclobutyl-2-(pyrimidine-2-base methoxyl group) phenyl] pyrazine-2-amine,

5-{3-[(4-bromobenzyl) oxygen base]-4-cyclobutyl-2-fluorophenyl } pyrazine-2-amine,

5-(4-{ [3-(5-Aminopyrazine-2-base)-6-cyclobutyl-2-fluorophenoxy] methyl } phenyl) pyrimidine-2-amine,

5-(the fluoro-3-{ of 4-cyclobutyl-2-[4'-(trifluoromethyl) phenylbenzene-4-base] methoxyl group } phenyl) pyrazine-2-amine,

5-[the fluoro-3-of 4-cyclohexyl-2-(pyrimidine-2-yloxy) phenyl] pyrimidine-2-amine and

5-{3-[(4-aminopyrimidine-2-base) oxygen base]-4-cyclohexyl-2-fluorophenyl } pyrimidine-2-amine.

5. a pharmaceutical composition, described pharmaceutical composition comprises compound according to any one of at least one claim 1-4 and the pharmaceutically acceptable carrier of at least one.

6. pharmaceutical composition according to claim 5, described pharmaceutical composition comprises at least one compound according to claim 4.

7. treatment suffers from or is diagnosed as a person under inspection's method for disease and/or the obstacle suffered from by the mediation of FLAP activity, and described method comprises the compound according to any one of at least one claim 1-4 to described person under inspection's administering therapeutic significant quantity.

8. method according to claim 7, wherein said disease and/or obstacle are selected from breathing, heart and cardiovascular, autoimmunization and supersensitivity, oncogenic disorder and/or obstacle and their related symptoms or complication.

9. method according to claim 8, wherein said respiratory disease and/or obstacle be selected from increase the weight of, non-allergic asthma, fibrotic lung disease, adult respiratory distress syndrome and chronic obstructive pulmonary disease or their related symptoms or complication.

10. method according to claim 8, wherein said heart and cardiovascular disorder and/or obstacle are selected from myocardial infarction, atherosclerosis and apoplexy aortic aneurysm, atherosclerosis or their related symptoms or complication.

11. methods according to claim 8, wherein said autoimmunization and anaphylactic disease and/or obstacle are selected from rheumatoid arthritis, inflammatory bowel, ephritis, joint of vertebral column inflammation, polymyositis, dermatomyositis, gouty overspill, systemic lupus erythematous, systemic sclerosis, Alzheimer, multiple sclerosis, allergic rhinitis, allergic dermatitis and asthma or their related symptoms or complication.

12. methods according to claim 8, wherein said oncogenic disorder and/or obstacle are selected from tumor cell proliferation, differentiation, apoptosis, tumor-associated vessels generate and the transfer of cancer cells or intrusion.

13. methods according to claim 7, the treatment significant quantity of the compound of its Chinese style (I) is that about 0.1mg/ agent is to about 5g/ agent.

14. 1 kinds of methods for the preparation of pharmaceutical composition, described method comprises and any one in compound according to claim 1 being mixed with pharmaceutically acceptable carrier.

15. 1 kinds of methods for the preparation of compound according to claim 1, wherein L is key, R ₁for cyclobutyl, ring A is , and R ₂for the phenyl be optionally substituted or 5 yuan or 6 yuan of heteroaryls being optionally substituted,

Described method comprises:

The compound of formula (II) and t-butyl-dimethylsilyl (TBS) muriate is made to react compound to generate corresponding formula (III) in the presence of solvent;

Under palladium catalyst exists, make the compound of formula (III) and cyclobutyl zinc bromide react compound to generate corresponding formula (IV);

Under acid and n-Butyl Lithium existence, make the compound of formula (IV) and triisopropyl borate ester react compound to generate corresponding formula (V);

Under catalyzer and alkali exist, make the compound of the compound of formula (V) and formula (VI) react compound to generate corresponding formula (VII).

16. methods according to claim 15, described method also comprises:

Under hexaoxacyclooctadecane-6-6 and alkali exist, make the compound of the compound of formula (VII) and formula (VIII) react compound to generate corresponding formula (I).